Cytochrome p450 inhibitors and uses thereof

ABSTRACT

The present invention provides compounds having the general structural formula (I) 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving fibrosis and proliferation, and where anti-fibrotic or anti-proliferative activity is beneficial.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/700,730, filed Nov. 28, 2012, which is a continuation ofInternational Application serial no. PCT/US2011/038695, filed Jun. 1,2011, which claims priority under 35 U.S.C. §119(e) to U.S. ProvisionalPatent Application Ser. Nos. 61/396,696, filed Jun. 1, 2010, and61/460,243, filed Dec. 29, 2010, all which are incorporated herein byreference in their entireties.

GOVERNMENT SUPPORT

This invention was made with government support under Grant No. NS045373awarded by the National Institutes of Health. The government has certainrights in the on.

BACKGROUND OF THE INVENTION

Numerous diseases and conditions responsible for significant morbidityas well as mortality have as an underlying disease mechanism theinappropriate or excessive production of fibrous connective tissue, aprocess generally known as fibrosis. Such diseases and conditionsinclude by way of non-limiting examples, fibrotic liver disease,cirrhosis, cardiac fibrosis and lung fibrosis including idiopathicpulmonary fibrosis, in addition to these, numerous other conditions anddiseases exhibit a fibrotic component, including but not limited tohepatic ischemia-reperfusion injury, cerebral infarction, chronicobstructive pulmonary diseases including emphysema, pancreatic fibrosis,ischemic heart disease, heart failure and renal disease including renalfibrosis. These conditions and diseases extract a major toll on thehealths of afflicted individuals, and on the health care system.

Furthermore, dysproliferative diseases including cancer are also majordiseases with significant impact to the patients as well as the healthcare system.

Means to affect the onset or progression of such conditions and diseaseswould be highly desirable.

SUMMARY OF THE INVENTION

In one embodiment, compounds are provided that are useful for, amongother purposes, the prevention, treatment or lessening of the severityof a condition or disease associated with or characterized by increased,excessive or inappropriate fibrosis, or characterized by cellulardysproliferation, represented by Formula (I):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, wherein:    -   X is an unsaturated heterocycle selected from pyrrolyl,        pyrazolyl, imidazolyl, triazolyl, benzimidazolyl,        benzotriazolyl, tetrazolyl, thiazole, 3-pyridinyl or        4-pyridinyl, any of which is optionally substituted with one or        more independent R⁶⁶ substituents;    -   R¹ is hydrogen, C₀₋₆alkyl, —OR⁷, —SR⁷, or —N⁷R⁸;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO—NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷—SO₂NR⁷¹R⁸¹        or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   Y is a bond, hydrogen, halogen, an oxygen atom, sulfur atom,        —CN, R⁷⁴, —C(═NR⁷⁴)NR⁷⁵R⁷⁶, —C(═NR⁷⁴)OR⁷⁵—, —COR⁷⁴, —R⁷⁴COR⁷⁵,        —CR⁷⁴R⁷⁵COR⁷⁶, —COOR⁷⁴, —R⁷⁴COOR⁷⁵, —CR⁷⁴R⁷⁵COOR⁷⁶, —CONR⁷⁴R⁷⁵,        —CR⁷⁴R⁷⁵CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —NR⁷⁴COR⁷⁵, —NR⁷⁴CONR⁷⁵R⁷⁶,        —SO₂CR⁷⁴R⁷⁵, —SO₂NR⁷⁴R⁷⁵, —NR⁷⁴SO₂NR⁷⁵R⁷⁶, —NR^(6b)CO—,        —NR^(6b)R⁷⁵, aryl or heteroaryl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, R⁶⁸, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶ substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,        -alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-,        -hetarylalkenyl-, or -alkenylhetaryl-, any of which is        optionally substituted with one or more independent halo, cyano,        hydroxy, nitro, R⁶⁸, C₁₋₁₀alkoxy, —COOR⁷⁴, —(C═O)N(R⁷⁴)—,        NR⁷⁴CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or        —NR⁷⁶R⁸⁶ substituents;    -   Q¹ is C₀₋₆alkyl, cycloC₃₋₈alkyl, bridged bicycloalkyl, OR⁷⁵,        —COR⁷⁴, —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), —CO₂R⁷⁵, —CONR⁷⁵R⁸⁵, —(C═S)OR⁷⁵,        —(C═O)SR⁷⁵, —NO₂, —CN, halo, —S(O)_(n6)R⁷⁵, —SO₂NR⁷⁵R⁸⁵,        —NR⁷⁵(C═NR⁷⁷⁵)NR⁷⁷⁷⁵R⁸⁵, —NR⁷⁵(C═NR⁷⁷⁵)OR⁷⁷⁷⁵,        —NR⁷⁵(C═NR⁷⁷⁵)SR⁷⁷⁷⁵, —O(C═O)OR⁷⁵, —O(C═O)NR⁷⁵R⁸⁵, —O(C═O)SR⁷⁵,        —S(C═O)OR⁷⁵, —S(C═O)NR⁷⁵R⁸⁵, —S(C═O)SR⁷⁵, —NR⁷⁵(C═O)NR⁷⁷⁵R⁸⁵, or        —NR⁷⁵(C═S)NR⁷⁷⁵R⁸⁵; in the case of —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), R⁷⁵ and        R⁸⁵ taken together with the nitrogen atom to which they are        attached form a 3-10 membered heterocyclic saturated ring; or        heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkyl_(C1-10)alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents,        or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or        R^(4b) with R^(5b), or R^(4c) with R^(5C), taken together with        the respective carbon atom to which they are attached, form a        carbonyl or 3-10 membered saturated or unsaturated monocyclic or        polycyclic ring, wherein said ring is optionally substituted        with R⁶⁹ or R^(4a) with R^(5a), or R^(4b) with R^(5b), or R^(4c)        with R^(5c), taken together with the respective carbon atom to        which they are attached, form a 3-10 membered saturated or        unsaturated monoheterocyclic or polyheterocyclic ring, wherein        said ring is optionally substituted with R⁶⁹;    -   R^(6a), R^(6b), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently        hydrogen, halo, —OR⁷⁷—SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸,        —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or        aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or        hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —OR⁷⁷,        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or        mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl,        —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in        the case of —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with        the nitrogen atom to which they are attached form a 3-10        membered mono or polycyclic saturated ring, mono or polycyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkyl C₁₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        halo C₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl) (C₀₋₄alkyl) substituents; or        mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or        —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, halo        C₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; and    -   n1, n2, n3, n4, n5, n6, and n7 are each independently equal to        0, 1 or 2.

In another embodiment, pharmaceutical compositions comprising acompound) of Formula (I) and a pharmaceutically acceptable carrier,excipient or diluent.

In further embodiment, a compound is represented by Formula (I), or an For Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof, wherein Yis nitrogen, and the other variables are as described above.

In further embodiment, compounds useful for the purposes describedherein are represented by Formula (II):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, and wherein all other substituents are as defined        herein above.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (II-A):

-   -   or an E or Z isomer thereof. syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof; and wherein all substituents are as defined herein        above.

In another embodiment, a compound is represented by Formula (I), or an Eor Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof, wherein Yis —NR^(6b)CO—, and the other variables are as described above.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (III):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, and wherein all substituents are as defined herein        above

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (III-A):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, and wherein all substituents are as defined herein        above

In another embodiment, a compound is represented by Formula (I), or an Eor Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof, wherein Yis oxygen, and the other variables are as described above.

In an embodiment of this fourth aspect, compounds useful for thepurposes described herein are represented by Formula (IV):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof and wherein all substituents are as defined herein        above

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (IV-A):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, and wherein all substituents are as defined herein        above.

In a further embodiment, a compound is represented by Formula (I), or anE or Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof, wherein Yis aryl or heteroaryl, and the other variables are as described above.

In a further embodiment, compounds useful for the purposes describedherein are represented by Formula (V):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, wherein:    -   B is aryl or heteroaryl which is optionally substituted with one        or more independent halo, —OR⁷⁷—SR⁷⁷, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7),        —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸,        C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl; or aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl C₂₋₁₀alkynyl,        haloC₂₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —OR⁷⁷,        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents:    -   and wherein all other substituents are as defined herein above.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (V-A):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, and wherein all other substituents are as defined        herein above.

In another embodiment, a compound is represented by Formula (I), or an Eor Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof, wherein Yis as described below and the other variables are as described above.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (VI):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, wherein:    -   Y is hydrogen, halogen, —OR⁷⁴, —SR⁷⁴, —R⁷⁴, —C(═NR⁷⁴)NR⁷⁵R⁷⁶,        —CN, —C(═NR⁷⁴)OR⁷⁵—, —COR⁷⁴, —R⁷⁴COR⁷⁵, —CR⁷⁴R⁷⁵COR⁷⁶, —COOR⁷⁴,        —R⁷⁴COOR⁷⁵, —CR⁷⁴R⁷⁵COOR⁷⁶, —CONR⁷⁴R⁷⁵, —CR⁷⁴R⁷⁵CONR⁷⁴R⁷⁵,        —NR⁷⁴COOR⁷⁵, —NR⁷⁴COR⁷⁵, —NR⁷⁴CONR⁷⁵R⁷⁶, —SO₂CR⁷⁴R⁷⁵,        —SO₂NR⁷⁴R⁷⁵, —NR⁷⁴SO₂NR⁷⁵R⁷⁶, —NR⁷⁴R⁷⁵, aryl or heteroaryl;    -   and wherein the other variables are as described above.

In another embodiment, the invention provides compositions includingpharmaceutical compositions of any of the compounds of Formulae (I)-(VI)disclosed herein. Such pharmaceutical compositions can comprise acarrier, excipient or diluent.

In another embodiment, the aforementioned formulae, compounds andpharmaceutical compositions have anti-fibrotic activities and thus areuseful for the prevention, treatment or lessening of the severity of acondition or disease associated with or characterized by increased,excessive or inappropriate fibrosis. In another embodiment, theaforementioned formulae, compounds and pharmaceutical formulations haveanti-dysproliferative activities and thus are useful for the prevention,treatment or lessening of the severity of a condition or diseaseassociated with or characterized by increased, excessive orinappropriate proliferation, such as cancer.

In another aspect, the invention provides methods for the use of any ofthe compounds disclosed herein for treating or lessening the severity ofa disease or condition associated with inappropriate fibrosis. Incertain embodiments, the method is for treating or lessening theseverity of a disease or condition selected from fibrotic liver disease,cirrhosis, cardiac fibrosis and lung fibrosis including idiopathicpulmonary fibrosis; hepatic ischemia-reperfusion injury, cerebralinfarction, chronic obstructive pulmonary diseases including emphysema,pancreatic fibrosis, ischemic heart disease, heart failure and renaldisease including renal fibrosis, fibrotic liver disease, hepaticischemia-reperfusion injury, cerebral infarction, ischemic heartdisease, and renal disease or lung (pulmonary) fibrosis. In certainembodiments, the method is for treating or lessening the severity of adisease or condition selected from liver fibrosis associated withhepatitis C, hepatitis B, delta hepatitis, chronic alcoholism,non-alcoholic steatohepatitis, extrahepatic obstructions (stones in thebile duet), cholangiopathies (primary biliary cirrhosis and sclerosingcholangitis), autoimmune liver disease, and inherited metabolicdisorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsindeficiency); damaged and/or ischemic organs, transplants or gratis;ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardialischemia; atherosclerosis; renal failure; renal fibrosis or idiopathicpulmonary fibrosis. In certain exemplary embodiments, the method is forthe treatment of wounds for acceleration of healing; vascularization ofa damaged and/or ischemic organ, transplant or graft, amelioration ofischemia/reperfusion injury in the brain, heart, liver, kidney, andother tissues and organs; normalization of myocardial perfusion as aconsequence of chronic cardiac ischemia or myocardial infarction;development or augmentation of collateral vessel development aftervascular occlusion or to ischemic tissues or organs; fibrotic diseases;hepatic disease including fibrosis and cirrhosis; lung fibrosis;radiocontrast nephropathy; fibrosis secondary to renal obstruction;renal trauma and transplantation; renal failure secondary to chronicdiabetes and/or hypertension; amytrophic lateral sclerosis, musculardystrophy, scleroderma, chronic obstructive pulmonary disease,emphysema, diabetes mellitus, multiple sclerosis, trauma to the centralnervous system, and hereditary neurodegenerative disorders including theleukodystrophies such as metachromatic leukodystrophy, Refsum's disease,adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavandisease, Pelizaeus-Merzbacher disease and Alexander's disease.

In addition, compounds of the invention are useful in the treatment ofdysproliferative diseases including cancer, psoriasis, rheumatoidarthritis, and other inflammatory joint and skin diseases. In oneembodiment, the compounds are useful in the treatment of prostatecancer. In one embodiment, the compounds are useful in the treatment ofbreast cancer, In one embodiment the compounds are useful in thetreatment of ovarian cancer.

In another embodiment, compounds of the invention are useful forprevention and treatment of other cancerous and precancerous conditions,including, for example, premalignant and malignant hyperproliferativediseases such as cancers of the breast, skin, prostate, colon, bladder,cervix, uterus, stomach, lung, esophagus, blood and lymphatic system,larynx, oral cavity, metaplasias, dysplasias, neoplasias, leukoplakiasand papillomas of the mucous membranes, and in the treatment of Kaposi'ssarcoma. In addition, inventive compounds can also be used as agents totreat diseases of the eye, including, for example, proliferativevitreoretinopathy, retinal detachment, corneopathies such as dry eye, aswell as in the treatment and prevention of various cardiovasculardiseases, including, without limitation, diseases associated with lipidmetabolism such as dyslipidemias, prevention of post-angioplastyrestenosis and as an agent to increase the level of circulation tissueplasminogen activator. Other uses include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts, various inflammatory diseases such as pulmonaryfibrosis, ileitis, colitis and Krohn's disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease and stroke,improper pituitary function, including insufficient production of growthhormone, modulation of apoptosis, including both the induction ofapoptosis, restoration of hair growth, including combination therapieswith the present compounds and other agents such as minoxidil, diseasesassociated with the immune systems, including use of the presentcompounds as immunosuppressant and immunostimulants, modulation of organtransplant rejection and facilitation of wound healing, includingmodulation of chelosis. Compounds are also useful eating type IInon-insulin dependent diabetes mellitus (NIDDM).

The present invention is also directed to treatment of non-malignanttumors and other disorders involving inappropriate cell or tissue growthby administering a therapeutically effective amount of an agent of theinvention. For example, it is contemplated that the invention is usefulfor the treatment of arteriovenous (AV) malformations, particularly inintracranial sites. The invention may also be used to treat psoriasis, adermatologic condition that is characterized by inflammation andvascular proliferation; benign prostatic hypertrophy, a conditionassociated with inflammation and possibly vascular proliferation; andcutaneous fungal infections. Treatment of other hyperproliferativedisorders is also contemplated. The agents may also be used topically toremove warts, birthmarks, moles, nevi, skin tags, lipomas, angiomasincluding hemangiomas, and other cutaneous lesions for cosmetic or otherpurposes.

Furthermore, the compounds embodied herein inhibit the activity ofcytochrome P450 (CYP) enzymes. In a further embodiment, the compoundsembodied herein inhibit CYP26. In a further embodiment, the compoundsembodied herein inhibit CYP17. In a further embodiment, the compoundsembodied herein inhibit CYP19. In a further embodiment, the compoundsembodied herein inhibit both CYP26 and CYP 1.7, and may be referred toas dual inhibitors or dual CYP26 and CYP17 inhibitors. In a furtherembodiment, the compounds embodied herein inhibit both CYP26 and CYP19,and may be referred to as dual inhibitors or dual CYP26 and CYP19inhibitors. Although disclosure of the mechanism by which embodimentsherein operate is not required nor are Applicants bound thereto,inhibitors of CYP26 increase the levels of all-trans retinoic acid(ATRA), which increase is beneficial in various conditions and diseasesas described herein, such as but not limited to the fibrotic process anddysproliferative diseases. Inhibitors of CYP17 decrease levels ofandrogens such as testosterone, which decrease is beneficial in variousconditions and diseases as described herein, such as but not limited tothe dysproliferative and inflammatory diseases, such as prostate cancer.Inhibitors of CYP19 decrease levels of estrogens, which decrease isbeneficial in various conditions and diseases as described herein, suchas but not limited to dysproliferative and inflammatory diseases, suchas breast and ovarian cancer.

In another embodiment, compounds of the invention as well ascompositions and formulations thereof are therapeutically beneficialwhen administered at a time after the onset of the acute disease oracute condition or time of injury. In certain instances administrationat least 3 hours after onset is beneficial. In other embodimentsadministration at least 24 hours after onset is beneficial. In certainother embodiments administration at least 1-3 weeks after onset isbeneficial. In other embodiments methods are provided for treating anacute disease or condition wherein compound is administered at a timeafter the onset or induction of the disease or condition. In otherembodiments, temporal separation of the induction, onset, recurrence orrecrudescence of a disease or injury, and the optimal effective responseto an antifibrotic or antidysproliferative compound, provides guidanceto the timing of administration of a compound of the invention or acomposition of formulation thereof. In other embodiments, a disease,condition or injury can be prevented by prophylactic administration of acompound embodied herein prior to the injury, exposure, or otheranticipated sustaining of pathology.

BRIEF DESCRIPTIONS OF THE DRAWINGS

FIG. 1 shows the effect of a compound embodied herein on liver functionin the thioacetic acid-induced liver fibrosis model in the mouse.

FIG. 2 shows the effect of a compound embodied herein on serumtestosterone levels in mice.

DEFINITIONS

Unless otherwise stated, the connections of compound name moieties areat the rightmost recited moiety. That is, the substituent name startswith a terminal moiety, continues with any bridging moieties, and endswith the connecting moiety. For example, hetarylthioC₁₋₄alkyl has aheteroaryl group connected through a thio sulfur to a C₁₋₄ alkyl thatconnects to the chemical species bearing the substituent.

As used herein, for example, “C₀₋₄alkyl” is used to mean an alkyl having0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branchedconfiguration. An alkyl having no carbon is hydrogen when the alkyl is aterminal group. An alkyl having no carbon is a direct bond when thealkyl is a bridging (connecting) group.

In all embodiments of this invention, the term “alkyl” includes bothbranched and straight chain alkyl groups. Typical alkyl groups aremethyl, ethyl, n-propyl, isopropyl (iPr), n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl,decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl andthe like.

The term “halo” or “halogen” refers to fluoro, chloro, bromo or iodo.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl,trifluoromethyl, perfluoropropyl, 8-chlorononyl and the like.

The term “cycloalkyl” or “saturated ring” refers to a cyclic aliphaticring structure, optionally substituted with alkyl, hydroxy and halo,such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl,2-hydroxycyclopentyl cyclohexyl, 4-chlorocyclohexyl, cycloheptyl,cyclooctyl and the like.

The term “bicycloalkyl” refers to two cycloalkyl rings fused togetherand the term “bridged bicycloalkyl” refers to two rings joined togetherforming a bridged structure, for example bicyclo[3.2.1]octane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and the like.

The term “alkylcarbonyloxyalkyl” refers to an ester moiety, for exampleacetoxymethyl, n-butyryloxyethyl and the like.

The term “alkynylcarbonyl” refers to an alkynylketo functionality, forexample propynoyl and the like.

The term “hydroxyalkyl” refers to an alkyl group substituted with one ormore hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl andthe like.

The term “alkylsulfonylalkyl” refers to an alkyl group substituted withan alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyland the like.

The term “alkylsulfonyl” refers to a sulfonyl moiety substituted with analkyl group, for example mesyl, n-propylsulfonyl and the like.

The term “acetylaminoalkyl” refers to an alkyl group substituted with anamide moiety, for example acetylaminomethyl and the like.

The term “acetylaminoalkenyl” refers to an alkenyl group substitutedwith an amide moiety, for example 2-(acetylamino)vinyl and the like.

The term “alkenyl” refers to an ethylenically unsaturated hydrocarbongroup, straight or branched chain, having 1 or 2 ethylenic bonds, forexample vinyl, allyl, 1-butenyl, 2-butenyl, isopropenyl, 2-pentenyl andthe like.

The term “haloalkenyl” refers to an alkenyl group substituted with oneor more halo groups.

The term “unsaturated ring” refers to a substituted or unsubstituted“cycloalkenyl” or a phenyl group.

The term “cycloalkenyl” refers to a cyclic aliphatic ring structure,optionally substituted with alkyl, hydroxy and halo, having 1 or 2ethylenic bonds such as methylcyclopropenyl,trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl,1,4-cyclohexadienyl and the like.

The term “alkynyl” refers to an unsaturated hydrocarbon group, straightor branched, having 1 or 2 acetylenic bonds, for example ethynyl,propargyl and the like.

The term “haloalkynyl” refers to an alkynyl group substituted with oneor more halo groups.

The term “alkylcarbonyl” refers to an alkylketo functionality, forexample acetyl, n-butyryl and the like.

The term “alkenylcarbonyl” refers to an alkenylketo functionality, forexample, propenoyl and the like.

The term “aryl” refers to phenyl or naphthyl which may be optionallysubstituted. Typical aryl groups include, but are not limited to,phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 3-chlorophenyl,3-fluorophenyl, 3-nitrophenyl, 3-(trifluoromethyl)phenyl,2-methoxyphenyl, 2-methylphenyl, 3-methyphenyl, 4-methylphenyl,4-ethylphenyl, 2-methyl-3-methoxyphenyl, 2,4-dibromophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl 2,4,6-trichlorophenyl,4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl,4-(trifluoromethyl)phenyl and 2-iodo-4-methylphenyl.

The term “heterocyclic unsaturated ring” refers to a substituted orunsubstituted “heteroaryl” or a heteroaliphatic ring structure having 1or 2 ethylenic bonds such as dihydropyridine, tetrahydropyridine,dihydropyrrole, dihydroimidazole and the like.

The terms “heteroaryl” or “hetaryl” refer to a substituted orunsubstituted 3-10 membered unsaturated ring containing one, two, threeor four heteroatoms, preferably one or two heteroatoms independentlyselected from oxygen, nitrogen and sulfur or to a bicyclic unsaturatedring system containing up to 10 atoms including at least one heteroatomselected from oxygen, nitrogen and sulfur. Examples of heteroarylsinclude, but are not limited to, 2-pyridinyl (synonym: 2-pyridyl),3-pyridinyl (synonym: 3-pyridyl) or 4-pyridinyl (synonym: 4-pyridyl),pyrazinyl, 2-, 4-, or 5-pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl,imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, andbenzothienyl. The heterocyclic ring may be optionally substituted withup to two substituents.

The terms “aryl-alkyl” or “arylalkyl” are used to describe a groupwherein the alkyl chain can be branched or straight chain with the arylportion, as defined hereinbefore, forming a bridging portion of thearyl-alkyl moiety. Examples of aryl-alkyl groups include, but are notlimited to, optionally substituted benzyl, phenethyl, phenpropyl andphenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl,2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl,2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl,2-(3-nitrophenyl)ethyl, 2(2,4-dichlorophenyl)ethyl,2-(3,5-dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-(3-chlorophenyl)propyl,3-(2-methylphenyl)propyl, 3-(4-methoxyphenyl)propyl, 3-(4-4trifluoromethyl)phenyl)propyl, 3-(2,4-dichlorophenyl)propyl,4-phenylbutyl, 4(4-chlorophenyl)butyl, 4(2-methylphenyl)butyl,4(2,4-dichlorophenyl)butyl, 4-(2-methoxyphenyl)butyl and 10-phenyldecyl.

The terms “aryl-cycloalkyl” or “arylcycloalkyl” are used to describe agroup wherein the aryl group is attached to a cycloalkyl group, forexample phenylcyclopentyl and the like.

The terms “aryl-alkenyl” or “arylalkenyl” are used to describe a groupwherein the alkenyl chain can be branched or straight chain with thearyl portion, as defined hereinbefore, forming a bridging portion of thearalkenyl moiety, for example styryl (2-phenylvinyl), phenpropenyl andthe like.

The terms “aryl-alkynyl” or “arylalkynyl” are used to describe a groupwherein the alkynyl chain can be branched or straight chain with thearyl portion, as defined hereinbefore, forming a bridging portion of thearyl-alkynyl moiety, for example 3-phenyl-1-propynyl and the like.

The terms “aryl-oxy” or “aryloxy” are used to describe a terminal angroup attached to a bridging oxygen atom. Typical aryl-oxy groupsinclude phenoxy, 3,4-dichlorophenoxy and the like.

The terms “aryl-oxyalkyl” or “aryloxyalkyl” are used to describe a groupwherein an alkyl group is substituted with an aryl-oxy group, forexample pentafluorophenoxymethyl and the like.

The terms “hetaryl-oxy” or “heteroaryl-oxy” or “hetaryloxy” or“heteroaryloxy” are used to describe a terminal hetaryl group attachedto a bridging oxygen atom. Typical hetaryl-oxy groups include4,6-dimethoxypyrimidin-2-yloxy and the like.

The terms “hetarylalkyl” or “heteroarylalkyl” or “hetaryl-alkyl” or“heteroaryl-alkyl” are used to describe a group wherein the alkyl chaincan be branched or straight chain with the heteroaryl portion, asdefined hereinbefore, forming a bridging portion of the heteroaralkylmoiety, for example 3-furylmethyl, thienyl, furfuryl and the like.

The terms “hetarylalkenyl” or “heteroarylalkenyl” or “hetaryl-alkenyl”or “heteroaryl-alkenyl” are used to describe a group wherein the alkenylchain can be branched or straight chain with the heteroaryl portion, asdefined hereinbefore, forming a bridging portion of the heteroaralkenylmoiety, for example 3-(4-pyridyl)-1-propenyl.

The terms “hetarylalkyl” or “heteroarylalkynyl” or “hetaryl-alkynyl” or“heteroaryl-alkynyl” are used to describe a group wherein the alkynylchain can be branched or straight chain with the heteroaryl portion, asdefined hereinbefore, forming a bridging portion of the heteroaralkynylmoiety, for example 4-(2-thienyl)-1-butynyl.

The term “heterocyclyl” or “heterocyclic saturated ring” refers to asubstituted or unsubstituted 3-10 membered saturated ring containingone, two or three heteroatoms, preferably one or two heteroatomsindependently selected from oxygen, nitrogen and sulfur or to a bicyclicring system containing up to 10 atoms including at least one heteroatomselected from oxygen, nitrogen and sulfur wherein the ring containingthe heteroatom is saturated. Examples of heterocyclyls include, but arenot limited to, tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl,piperidinyl, 4-pyranyl, tetrahydropyranyl, thiolanyl, morpholinyl,piperazinyl, dioxolanyl, dioxanyl, indolinyl and 5-methyl-6-chromanyl.

The term “monoheterocyclic” refers to a single heterocyclic ringstructure, while “polyheterocyclic” refers to more than one ring fusedtogether to form a heterocyclic structure.

The terms “heterocyclylalkyl” or “heterocyclyl-alkyl” are used todescribe a group wherein the alkyl chain can be branched or straightchain with the heterocyclyl portion, as defined hereinabove, forming abridging portion of the heterocyclylalkyl moiety, for example3-piperidinylmethyl and the like.

The terms “heterocyclylalkenyl” or “heterocyclyl-alkenyl” are used todescribe a group wherein the alkenyl chain can be branched or straightchain with the heterocyclyl portion, as defined hereinbefore, forming abridging portion of the heterocyclylalkenyl moiety, for example2-morpholinyl-1-propenyl.

The terms “heterocyclylalkynyl” or “heterocyclyl-alkynyl” are used todescribe a group wherein the alkynyl chain can be branched or straightchain with the heterocyclyl portion, as defined hereinbefore, forming abridging portion of the heterocyclylalkynyl moiety, for example2-pyrrolidinyl-1-butynyl.

The term “carboxylalkyl” includes both branched and straight chain alkylgroups as defined hereinbefore attached to a carboxyl (—COOH) group.

The term “carboxylalkenyl” includes both branched and straight chainalkenyl groups as defined hereinbefore attached to a carboxyl (—COOH)group.

The term “carboxylalkynyl” includes both branched and straight chainalkynyl groups as defined hereinbefore attached to a carboxyl (—COOH)group.

The term “carboxylcycloalkyl” refers to a carboxyl (—COOH) groupattached to a cyclic aliphatic ring structure as defined hereinbefore.

The term “carboxylcycloalkenyl” refers to a carboxyl (—COOH) groupattached to a cyclic aliphatic ring structure having 1 or 2 ethylenicbonds as defined hereinbefore.

The terms “cycloalkylalkyl” or “cycloalkyl-alkyl” refer to a cycloalkylgroup as defined hereinbefore attached to an alkyl group, for examplecyclopropylmethyl, cyclohexylethyl and the like.

The terms “cycloalkylalkenyl” or “cycloalkyl-alkenyl” refer to acycloalkyl group as defined hereinbefore attached to an alkenyl group,for example cyclohexylvinyl, cycloheptylallyl and the like.

The terms “cycloalkylalkynyl” or “cycloalkyl-alkynyl” refer to acycloalkyl group as defined hereinbefore attached to an alkynyl group,for example cyclopropylpropargyl, 4-cyclopentyl-2-butynyl and the like.

The terms “cycloalkenylalkyl” or “cycloalkenyl-alkyl” refer to acycloalkenyl group as defined hereinbefore attached to an alkyl group,for example 2(cyclopenten-1-yl)ethyl and the like.

The terms “cycloalkenylalkenyl” or “cycloalkenyl-alkenyl” refer to acycloalkenyl group as defined hereinbefore attached to an alkenyl group,for example 1-(cyclohexen-3-yl)allyl and the like.

The terms “cycloalkenylalkynyl” or “cycloalkenyl-alkynyl” refer to acycloalkenyl group as defined hereinbefore attached to an alkynyl group,for example 1-(cyclohexen-3-yl)propargyl and the like.

The term “carboxylcycloalkylalkyl” refers to a carboxyl (—COOH) groupattached to the cycloalkyl ring portion of a cycloalkylalkyl group asdefined hereinbefore.

The term “carboxylcycloalkylalkenyl” refers to a carboxyl (—COOH) groupattached to the cycloalkyl ring portion of a cycloalkylalkenyl group asdefined hereinbefore.

The term “carboxylcycloalkylalkynyl” refers to a carboxyl (—COOH) groupattached to the cycloalkyl ring portion of a cycloalkylalkynyl group asdefined hereinbefore.

The term “carboxylcycloalkenylalkyl” refers to a carboxyl (—COOH) groupattached to the cycloalkenyl ring portion of a cycloalkenylalkyl groupas defined hereinbefore.

The term “carboxylcycloalkenylalkenyl” refers to a carboxyl (—COOH)group attached to the cycloalkenyl ring portion of a cycloalkenylalkenylgroup as defined hereinbefore.

The term “carboxylcycloalkenylalkynyl” refers to a carboxyl (—COOH)group attached to the cycloalkenyl ring portion of a cycloalkenylalkynylgroup as defined hereinbefore.

The term “alkoxy” includes both branched and straight chain terminalalkyl groups attached to a bridging oxygen atom. Typical alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, tort-butoxy and thelike.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halo groups, for example chloromethoxy, trifluoromethoxy,difluoromethoxy, perfluoroisobutoxy and the like.

The term “alkoxyalkoxyalkyl” refers to an alkyl group substituted withan alkoxy moiety which is in turn substituted with a second alkoxymoiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl and thelike.

The term “alkylthio” includes both branched and straight chain alkylgroups attached to a bridging sulfur atom, for example methylthio.

The term “haloalkylthio” refers to an alkylthio group substituted withone or more halo groups, for example trifluoromethylthio.

The term “alkoxyalkyl” refers to an alkyl group substituted with alkoxygroup, for example isopropoxymethyl.

The term “alkoxyalkenyl” refers to an alkenyl group substituted with analkoxy group, for example 3-methoxyallyl.

The term “alkoxyalkynyl” refers to an alkynyl group substituted with analkoxy group, for example 3-methoxypropargyl.

The term “alkoxycarbonylalkyl” refers to a straight chain or branchedalkyl substituted with an alkoxycarbonyl, for exampleethoxycarbonylmethyl, 2-(methoxycarbonyl)propyl and the like.

The term “alkoxycarbonylalkenyl” refers to a straight chain or branchedalkenyl as defined hereinbefore substituted with an alkoxycarbonyl, forexample 4-(ethoxycarbonyl)-2-butenyl and the like.

The term “alkoxycarbonylalkynyl” refers to a straight chain or branchedalkynyl as defined hereinbefore substituted with an alkoxycarbonyl, forexample 4-(ethoxycarbonyl)-2-butynyl and the like.

The term “haloalkoxyalkyl” refers to a straight chain or branched alkylas defined hereinbefore substituted with a haloalkoxy, for example2-chloroethoxymethyl, trifluoromethoxymethyl and the like.

The term “haloalkoxyalkenyl” refers to a straight chain or branchedalkenyl as defined hereinbefore substituted with a haloalkoxy, forexample 4-(chloromethoxy)-2-butenyl and the like.

The term “haloalkoxyalkynyl” refers to a straight chain or branchedalkynyl as defined hereinbefore substituted with a haloalkoxy, forexample 4-(2-fluoroethoxy)-2-butynyl and the like.

The term “alkylthioalkyl” refers to a straight chain or branched alkylas defined hereinbefore substituted with an alkylthio group, for examplemethylthiomethyl, 3-(isobutylthio)heptyl and the like.

The term “alkylthioalkenyl” refers to a straight chain or branchedalkenyl as defined hereinbefore substituted with an alkylthio group, forexample 4-(methylthio)-2-butenyl and the like.

The term “alkylthioalkynyl” refers to a straight chain or branchedalkynyl as defined hereinbefore substituted with an alkylthio group, forexample 4-(ethylthio)-2-butynyl and the like.

The term “haloalkylthioalkyl” refers to a straight chain or branchedalkyl as defined hereinbefore substituted with an haloalkylthio group,for example 2-chloroethylthiomethyl, trifluoromethylthiomethyl and thelike.

The term “haloalkylthioalkenyl” refers to a straight chain or branchedalkenyl as defined hereinbefore substituted with an haloalkylthio group,for example 4-(chloromethylthio)-2-butenyl and the like.

The term “haloalkylthioalkynyl” refers to a straight chain or branchedalkynyl as defined hereinbefore substituted

The term “dialkoxyphosphorylalkyl” refers to two straight chain orbranched alkoxy groups as defined hereinbefore attached to a pentavalentphosphorous atom, containing an oxo substituent, which is in turnattached to an alkyl, for example diethoxyphosphorylmethyl.

The term “oligomer” refers to a low-molecular weight polymer, whosenumber average molecular weight is typically less than about 5000 g/mol,and whose degree of polymerization (average number of monomer units perchain) is greater than one and typically equal to or less than about 50.

Compounds described herein may contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula (I) is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula (I) and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included.

During the course of the synthetic procedures used to prepare suchcompounds, or in using racemization or epimerization procedures known tothose skilled in the art, the products of such procedures can be amixture of stereoisomers.

Within the enantiomers of the compounds, both the syn and anti isomersinvolving the X and G¹ substituent show activity. Furthermore, it ispreferable that there be dual chiral centers at the X and G¹ attachmentpositions, if G¹ is not hydrogen.

The invention also encompasses a pharmaceutical composition that iscomprised of a compound of Formula (I) in combination with apharmaceutically acceptable carrier.

Such a composition is comprised of a pharmaceutically acceptablecarrier, excipient or diluent, and a non-toxic therapeutically effectiveamount of a compound of Formula (I) as described above, or an E or Zisomer thereof, syn or anti isomer thereof, an optically pure isomerthereof, or a pharmaceutically acceptable salt thereof.

Moreover, within this embodiment, the invention encompasses apharmaceutical composition for the treatment of disease by inhibitingthe cytochrome retinoic acid 4-hydroxylase enzyme (CYP26) or byinhibiting cytochrome P450 17alpha-hydroxylase/C_(17,20)-lyase enzyme(CYP17), or in certain instances inhibiting both CYP26 and CYP17,comprising a pharmaceutically acceptable carrier and a non-toxictherapeutically effective amount of compound of Formula (I) as describedabove or a pharmaceutically acceptable salt thereof. In otherembodiments, the invention encompasses pharmaceuticals compositions forthe treatment of disease by inhibiting the cytochrome aromatase enzyme(CYP19). In other embodiments, pharmaceutical compositions are providedfor inhibiting both CYP26 and CYP19, comprising a pharmaceuticallyacceptable carrier and a non-toxic therapeutically effective amount ofcompound of Formula (I) as described above or a pharmaceuticallyacceptable salt thereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium slats. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N′,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylameine, trimethylamine,tripropylamine, komethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, formic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Preferred are citric, hydrobromic, formic, hydrochloric, maleic,phosphoric, sulfuric and tartaric acids. Particularly preferred areformic and hydrochloric acid.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula (I) (or E or Z isomer thereof, syn oranti isomer thereof, an optically pure isomer thereof, or apharmaceutically acceptable salt thereof) as an active ingredient, apharmaceutically acceptable carrier and optionally other therapeuticingredients or adjuvants. The compositions include compositions suitablefor oral, rectal, topical, and parenteral (including subcutaneous,intramuscular, and intravenous) administration, although the mostsuitable route in any given case will depend on the particular host, andnature and severity of the conditions for which the active ingredient isbeing administered. The pharmaceutical compositions may be convenientlypresented in unit dosage form and prepared by any of the methods wellknown in the art of pharmacy.

The phrase, “pharmaceutically acceptable derivative”, as used herein,denotes any pharmaceutically acceptable salt, ester, or salt of suchester, of such compound, or any other adduct or derivative which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound as otherwise described herein, or a metabolite orresidue thereof. Pharmaceutically acceptable derivatives thus includeamong others pro-drugs. A pro-drug is a derivative of a compound,usually with significantly reduced pharmacological activity, whichcontains an additional moiety, which is susceptible to removal in vivoyielding the parent molecule as the pharmacologically active species. Anexample of a pro-drug is an ester, which is cleaved in vivo to yield acompound of interest. Another example is an N-methyl derivative of acompound, which is susceptible to oxidative metabolism resulting inN-demethylation. Pro-drugs of a variety of compounds, and materials andmethods for derivatizing the parent compounds to create the pro-drugs,are known and may be adapted to the present invention. Certain exemplarypharmaceutical compositions and pharmaceutically acceptable derivativeswill be discussed in more detail herein below.

The term “tautomerization” refers to the phenomenon wherein a proton ofone atom of a molecule shifts to another atom. See, Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms and Structures, FourthEdition, John Wiley & Sons, pages 69-74 (1992). The term “tautomer” asused herein, refers to the compounds produced by the proton shift. Thus,the present invention encompasses the tautomeric moieties likepyrazoles, pyridones and enols, etc.

The term “geometrical isomers” refers to cis-trans isomerism, syn-antior E/Z isomerism based on the Cahn-Ingold-Prelog system. See March'sAdvanced Organic Chemistry: Reactions, Mechanisms and Structures, SixthEdition, Wiley-Interscience, pages 182-195 (2007). The term “geometricalisomers” as used herein, refers to compounds having double bond with anE or Z configuration or cis-trans isomers of monocyclic or fused ringsystems.

By the term “protecting group”, as used herein, it is meant that aparticular functional moiety, e.g., O, S, or N, is temporarily blockedso that a reaction can be carried out selectively at another reactivesite in a multifunctional compound. In preferred embodiments, aprotecting group reacts selectively in good yield to give a protectedsubstrate that is stable to the projected reactions; the protectinggroup must be selectively removed in good yield by readily available,preferably nontoxic reagents that do not attack the other functionalgroups; the protecting group forms an easily separable derivative (morepreferably without the generation of new stereogenic centers); and theprotecting group has a minimum of additional functionality to avoidfurther sites of reaction. As detailed herein, oxygen, sulfur, nitrogenand carbon protecting groups may be utilized. For example, in certainembodiments, as detailed herein, certain exemplary oxygen protectinggroups are utilized. These oxygen protecting groups include, but are notlimited to methyl ethers, substituted methyl ethers (e.g. MOM(methoxymethyl ether), MTM (methylthiomethyl ether), BOM(benzyloxymethyl ether), PMBM or MPM (p-methoxybenzyloxymethyl ether),to name a few), substituted ethyl ethers, substituted benzyl ethers,silyl ethers (e.g., TMS (trimethylsilyl ether), TES(triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS(t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS(t-butyldiphenyl silyl ether), to name a few), esters (e.g., formate,acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name afew), carbonates, cyclic acetals and ketals. In certain other exemplaryembodiments, nitrogen protecting groups are utilized. These nitrogenprotecting groups include, but are not limited to, carbamates (includingmethyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name afew) amides, cyclic imide derivatives, N-Alkyl and N-Aryl amines, iminederivatives, and enamine derivatives, to name a few. Certain otherexemplary protecting groups are detailed herein, however, it will beappreciated that the present invention is not intended to be limited tothese protecting groups; rather, a variety of additional equivalentprotecting groups can be readily identified using the above criteria andutilized in the present invention. Additionally, a variety of protectinggroups are described in “Protective Groups in Organic Synthesis” ThirdEd. Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York: 9the entire contents of which are hereby incorporated by reference.

As used herein, the term “isolated” when applied to the compounds of thepresent invention, refers to such compounds that are (i) separated fromat least some components with which they are associated in nature orwhen they are made and/or (ii) produced, prepared or manufactured by thehand of man.

As used herein the term “biological sample” includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from an animal (e.g., mammal) or extracts thereof; and blood,saliva, urine, feces, semen, tears, or other body fluids or extractsthereof; or purified versions thereof. For example, the term “biologicalsample” refers to any solid or fluid sample obtained from, excreted byor secreted by any living organism, including single-celled microorganisms (such as bacteria and yeasts) and multicellular organisms(such as plants and animals, for instance a vertebrate or a mammal, andin particular a healthy or apparently healthy human subject or a humanpatient affected by a condition or disease to be diagnosed orinvestigated). The biological sample can be in any form, including asolid material such as a tissue, cells, a cell pellet, a cell extract,cell homogenates, or cell fractions; or a biopsy, or a biological fluid.The biological fluid may be obtained from any site (e.g. blood, saliva(or a mouth wash containing buccal cells), tears, plasma, serum, urine,bile, seminal fluid, cerebrospinal fluid, amniotic fluid, peritonealfluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor,or any bodily secretion), a transudate, an exudate (e.g. fluid obtainedfrom an abscess or any other site of infection or inflammation), orfluid obtained from a joint (e.g. a normal joint or a joint affected bydisease such as rheumatoid arthritis, osteoarthritis, gout or septicarthritis). The biological sample can be obtained from any organ ortissue (including a biopsy or autopsy specimen) or may comprise cells(whether primary cells or cultured cells) or medium conditioned by anycell, tissue or organ. Biological samples may also include sections oftissues such as frozen sections taken for histological purposes.Biological samples also include mixtures of biological moleculesincluding proteins, lipids, carbohydrates and nucleic acids generated bypartial or complete fractionation of cell or tissue homogenates.Although the sample is preferably taken from a human subject, biologicalsamples may be from any animal, plant, bacteria, virus, yeast, etc. Theterm animal, as used herein, refers to humans as well as non-humananimals, at any stage of development, including, for example, mammals,birds, reptiles, amphibians, fish, worms and single cells. Cell culturesand live tissue samples are considered to be pluralities of animals. Incertain exemplary embodiments, the non-human animal is a mammal (e.g., arodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep,cattle, a primate, or a pig). An animal may be a transgenic animal or ahuman clone. If desired, the biological sample may be subjected topreliminary processing, including preliminary separation techniques.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS

Numerous diseases and conditions responsible for significant morbidityas well as mortality have as an underlying disease mechanism theinappropriate or excessive production of fibrous connective tissue, aprocess generally known as fibrosis. Such diseases and conditionsinclude fibrotic liver disease, cirrhosis, cardiac fibrosis, pancreaticfibrosis and lung fibrosis including idiopathic pulmonary fibrosis. Inaddition to these, numerous other conditions and diseases exhibit afibrotic component, including but not limited to hepaticischemic-reperfusion injury, cerebral infarction, ischemic heartdisease, heart failure and renal disease including renal fibrosis.Compounds embodied herein and pharmaceutical compositions comprisingthem are useful for the prevention or treatment of such conditions anddiseases.

In addition, effects on dysproliferative diseases such as cancer andskin diseases are also benefits of the compounds herein. In oneembodiment, compounds embodied herein are useful for the treatment ofprostate cancer and in particular castration-resistant prostate cancer.In another embodiment, compounds are useful for the treatment of breastcancer. In another embodiment, compounds are useful for the treatment ofovarian cancer, in another embodiment, compounds of the invention arealso useful for prevention and treatment of other cancerous andprecancerous conditions, including, for example, premalignant andmalignant hyperproliferative diseases such as cancers of the breast,skin, prostate, colon, bladder, cervix, uterus, stomach, lung,esophagus, blood and lymphatic system, larynx, oral cavity, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes, and in the treatment of Kaposi's sarcoma. In addition,inventive compounds can also be used as agents to treat diseases of theeye, including, for example, proliferative vitreoretinopathy, retinaldetachment, corneopathies such as dry eye, as well as in the treatmentand prevention of various cardiovascular diseases, including, withoutlimitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulation tissue plasminogen activator. Otheruses include the prevention and treatment of conditions and diseasesassociated with human papilloma virus (HMO, including warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis, restoration of hair growth,including combination therapies with the present compounds and otheragents such as minoxidil, diseases associated with the immune systems,including use of the present compounds as immunosuppressant andimmunostimulants, modulation of organ transplant rejection andfacilitation of wound healing, including modulation of chelosis.Compounds have also been discovered to be useful in treating type IInon-insulin dependent diabetes mellitus (NIDDM).

The present invention is also directed to treatment of non-malignanttumors and other disorders involving inappropriate cell or tissue growthby administering a therapeutically effective amount of an agent of theinvention. For example, it is contemplated that the invention is usefulfor the treatment of arteriovenous (AV) malformations, particularly inintracranial sites. The invention may also be used to treat psoriasis, adermatologic condition that is characterized by inflammation andvascular proliferation; benign prostatic hypertrophy, a conditionassociated with inflammation and possibly vascular proliferation; andcutaneous fungal infections. Treatment of other hyperproliferativedisorders is also contemplated. The agents may also be used topically toremove warts, birthmarks, moles, nevi, skin tags, lipomas, angiomasincluding hemangiomas, and other cutaneous lesions for cosmetic or otherpurposes.

Compounds embodied herein and pharmaceutical compositions comprisingthem are useful for the prevention or treatment of such conditions anddiseases.

Compounds of this invention include those generally set forth above anddescribed specifically herein, and are illustrated in part by thevarious classes, subgenera and species disclosed herein.

Additionally, the present invention provides pharmaceutically acceptablederivatives of the inventive compounds, and methods of treating asubject using these compounds, pharmaceutical compositions thereof, oreither of these in combination with one or more additional therapeuticagents.

1) General Description of Compounds of the Invention

In one embodiment, compounds useful for the purposes described hereinare represented by formula (I)

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, wherein:    -   X is an unsaturated heterocycle selected from pyrrolyl,        pyrazolyl, imidazolyl, triazolyl, benzimidazolyl,        benzotriazolyl, tetrazolyl, thiazole, 3-pyridinyl or        4-pyridinyl, any of which is optionally substituted with one or        more independent R⁶⁶ substituents;    -   R¹ is hydrogen, C₀₋₆alkyl, —OR⁷, —SR⁷, or —NR⁷R⁸;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl. C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷—SO₂NR⁷¹R⁸¹        or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   Y is a bond, hydrogen, halogen, an oxygen atom, sulfur atom,        —CN, R⁷⁴, —C(═NR⁷⁴)NR⁷⁵R⁷⁶, —C(—NR⁷⁴)OR⁷⁵—, —COR⁷⁴, —R⁷⁴COR⁷⁵,        —CR⁷⁴R⁷⁵COR⁷⁶, —COOR⁷⁴, —R⁷⁴COOR⁷⁵, —CR⁷⁴R⁷⁵COOR⁷⁶, —CONR⁷⁴R⁷⁵,        —CR⁷⁴R⁷⁵CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —NR⁷⁴COR⁷⁵, —NR⁷⁴CONR⁷⁵R⁷⁶,        —SO₂CR⁷⁴R⁷⁵, —SO₂NR⁷⁴R⁷⁵, —NR⁷⁴SO₂NR⁷⁵R⁷⁶, —NR^(6b)CO—,        —NR^(6b)R⁷⁵, aryl or heteroaryl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, R⁶⁸, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶ substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,        -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-,        -alkenylhetaryl-, or -aryl-, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, R⁶⁸, C₁₋₁₀alkoxy, —COOR⁷⁴, —(C═O)N(R⁷⁴)—, —NR⁷⁴CONR⁷⁴R⁷⁵,        —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or —NR⁷⁶R⁸⁶        substituents;    -   Q¹ is C₀₋₆alkyl, cycloC₃₋₈alkyl, bridged bicycloalkyl, —OR⁷⁵,        —COR⁷⁴, —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), —CO₂R⁷⁵, —CONR⁷⁵R⁸⁵, —(C═S)OR⁷⁵,        —(C═O)SR⁷⁵, —NO₂, —CN, halo, —S(O)_(n6)R⁷⁵, —SO₂NR⁷⁵R⁸⁵,        —NR⁷⁵(C═NR⁷⁷⁵)NR⁷⁷⁷⁵R⁸⁵, —NR⁷⁵(C═NR⁷⁷⁵)OR⁷⁷⁷⁵,        —NR⁷⁵(C═NR⁷⁷⁵)SR⁷⁷⁷⁵, —O(C═O)OR⁷⁵, —O(C═O)NR⁷⁵R⁸⁵, —O(C═O)SR⁷⁵,        —S(C═O)OR⁷⁵, —S(C═O)NR⁷⁵R⁸⁵, —S(C═O)SR⁷⁵, —NR⁷⁵(C═O)NR⁷⁷⁵R⁸⁵, or        —NR⁷⁵(C═S)NR⁷⁷⁵R⁸⁵; in the case of —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), R⁷⁵ and        R⁸⁵ taken together with the nitrogen atom to which they are        attached form a 3-10 membered heterocyclic saturated ring, or        heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocycyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents;        or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl. —CONR⁷⁷R⁸⁷, —SO₂N⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or R^(4a) with R^(5a), or R^(4b) with R^(5b), or        R^(4c) with R^(5C), taken together with the respective carbon        atom to which they are attached, form a carbonyl or 3-10        membered saturated or unsaturated monocyclic or polycyclic ring,        wherein said ring is optionally substituted with R⁶⁹; or R^(4a)        with R^(5a), or R^(4b) with R^(5b), or R^(4c) with R^(5c), taken        together with the respective carbon atom to which they are        attached, form a 3-10 membered saturated or unsaturated        monoheterocyclic or polyheterocyclic ring, wherein said ring is        optionally substituted with R⁶⁹;    -   R^(6a), R^(6b), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently        hydrogen, halo, —OR⁷⁷—SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸,        —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₀₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkyl, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)        (C₀₋₄alkyl) substituents; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₁₀alkenyl, haloC₂₋₁₀alkynyl,        —COOH, C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; and    -   n1, n2, n3, n4, n5, n6, and n7 are each independently equal to        0, 1 or 2.

In another embodiment, a compound is represented by Formula (I), or apharmaceutically acceptable salt thereof, wherein X is an optionallysubstituted imidazolyl, optionally substituted triazolyl, optionallysubstituted 3-pyridinyl, optionally substituted 4-pyridinyl and theother variables are as described above.

In another embodiment, a compound is represented by Formula (I), or apharmaceutically acceptable salt thereof, wherein X is a substitutedimidazolyl, substituted 3-pyridinyl, substituted 4-pyridinyl orsubstituted triazolyl; R¹ is hydrogen; and the other variables are asdescribed above.

In another embodiment of the present invention, a compound isrepresented by Formula (I), or an E or Z isomer thereof, syn or antiisomer thereof, an optically pure isomer thereof, or pharmaceuticallyacceptable salt thereof, wherein Y is nitrogen, and the other variablesare as described above.

Non-limiting examples of compounds of Formula (I) include3-(((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid:3-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoicacid;4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicacid;4-(((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid;4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicacid; Isopropyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;Isopropyl4(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;Ethyl3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;Methyl3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate,Isopropyl 3((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoate;Methyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate;Methyl4-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;Methyl4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate;1-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutanecarboxylicacid;1-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclohexanecarboxylicacid;1-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopentanecarboxylicacid; 3((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid;5-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-4-oxobutanoicacid;4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid;((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopropanecarboxylicacid;5-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-5-oxopentanoicacid; Ethyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutanecarboxylate;Methyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclohexanecarboxylate;Methyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopentanecarboxylate;Methyl3-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate;Methyl4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate;Methyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopropanecarboxylate;Methyl5-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-5-oxopentanoate;N-(6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)bicyclo[2.2.1]heptane-2-carboxamide;Methyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate;Methyl4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate;3-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoicacid;4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoicacid;2-Chloro-4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;2-Chloro-5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-(trifluoromethyl)benzoicacid;3-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-fluorobenzoicacid;3-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-(Ethyl(methyl)amino)-1-(H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid; 4-(6-(1-(1H-1,2,4-Triazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid; 4-(6-(1-(Pyridin-3-yl)butyl)benzo[d]thiazol-2-yl)benzoic acid;4-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;4-(6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;4-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;5-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2-fluorobenzoicacid; Methyl2-chloro-4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl2-chloro-5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-(trifluoromethyl)benzoate;Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-fluorobenzoate;Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl3-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl3-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl4-(6-(1-(1H-1,2,4-triazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl 4-(6-(1-(pyridin-3-yl)butyl)benzo[d]thiazol-2-yl)benzoate; Methyl4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl4-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl5-(6-(2-(dimethylamino)-1-(1H-indazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2-fluorobenzoate;1-(2-(3-(2H-Tetrazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;1-(2-(4-(2H-Tetrazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;methyl2-chloro-4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;methyl2-chloro-5-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;2-(4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)phenyl)aceticacid; methyl2-(4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)phenyl)acetate;2-chloro-4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;2-chloro-5-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylicacid; 6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylicacid; Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylate;Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carbimidate;Ethyl(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamate;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxamide;N-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide;1-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea;1-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2,2,2-trifluoroethanone;1-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2,2,2-trifluoroethanone;1-(1H-Imidazol-1-yl)-N,N-dimethyl-1-(2-phenylbenzo[d]thiazol-6-yl)butan-2-amine;1-(2-Bromobenzo[d]thiazol-1-yl)-N,N-dimethyl butan-2-amine;1-(2-Bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine;1-(2-Chlorobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;1-(2-Chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine;1-(Benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2(3H)-one;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2(3H)-one;1-(1H-Imidazol-1-yl)-1-(2-methoxybenzo[d]thiazol-6-yl)-N,N-dimethylbutan-2-amine;1-(1H-Imidazol-1-yl)-N,N-dimethyl-1-(2-methylbenzo[d]thiazol-6-yl)butan-2-amine;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)-2-methoxybenzo[d]thiazole;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)-2-methylbenzo[d]thiazole;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;2-Bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)-2-phenylbenzo[d]thiazole;2-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)aceticacid; 6-(1-(1H-1,2,4-triazol-1-yl)butyl)-2-bromobenzo[d]thiazole and2-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)aceticacid.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (II):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, wherein:    -   X is an unsaturated heterocycle selected from pyrrolyl,        pyrazolyl, triazolyl, benzimidazolyl, benzotriazolyl,        tetrazolyl, thiazole, 3-pyridinyl or 4-pyridinyl, any of which        is optionally substituted with one or more independent R⁶⁶        substituents;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkylC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆aminocarbonyl, mono(aryl)aminocarbonyl;        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₁₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷—SO₂NR⁷¹R⁸¹        or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   Z is -aryl-, arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,        -alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-,        -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is        optionally substituted with one or more independent halo, cyano,        hydroxy, nitro, R⁶⁸, C₁₋₁₀alkoxy, —COOR⁷⁴, —(C═O)N(R⁷⁴)—,        —NR⁷⁴CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or        —NR⁷⁶R⁸⁶ substituents;    -   Q¹ is C₀₋₆alkyl, cycloC₃₋₈alkyl, bridged bicycloalkyl, —OR⁷⁵,        —COR⁷⁴, —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), —CO₂R⁷⁵, —CONR⁷⁵R⁸⁵, —(C═S)OR⁷⁵,        —(C═O)SR⁷⁵, —NO₂, —CN, halo, —S(O)_(n6)R⁷⁵, —SO₂NR⁷⁵R⁸⁵,        —NR⁷⁵(C═NR⁷⁷⁵)NR⁷⁷⁵R⁸⁵, —NR⁷⁵(C═NR⁷⁷⁵)OR⁷⁷⁷⁵,        —NR⁷⁵(C═NR⁷⁷⁵)SR⁷⁷⁷⁵, —O(C═O)OR⁷⁵, —O(C═O)NR⁷⁵R⁸⁵, —O(C═O)SR⁷⁵,        —S(C═O)OR⁷⁵, —S(C═O)NR⁷⁵R⁸⁵, —S(C═O)SR⁷⁵, —NR⁷⁵(C═O) NR⁷⁷⁵R⁸⁵,        or —NR⁷⁵(C═S)NR⁷⁷⁵R⁸⁵; in the case of —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), R⁷⁵        and R⁸⁵ taken together with the nitrogen atom to which they are        attached form a 3-10 membered heterocyclic saturated ring, or        heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkynyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents;        or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —R⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, C haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) or R^(5a), or        R^(4b) with R^(5b), or R^(4c) with R^(5C), taken together with        the respective carbon atom to which they are attached, form a        carbonyl or 3-10 membered saturated or unsaturated monocyclic or        polycyclic ring, wherein said ring is optionally substituted        with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b), or        R^(4c) with R^(5c), taken together with the respective carbon        atom to which they are attached, form a 3-10 membered saturated        or unsaturated monoheterocyclic or polyheterocyclic ring,        wherein said ring is optionally substituted with R⁶⁹;    -   R^(6a), R^(6b), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently        hydrogen, halo, —OR⁷⁷—SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸,        —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or        aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocycyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆alkylaminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₁₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₁₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl) (C₀₋₄alkyl)        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₂₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl) (C₀₋₄alkyl) substituents; and    -   n1, n2, n3, n4, n5, n6, and n7 are each independently equal to        0, 1 or 2.

In another embodiment compounds useful for the purposes described hereinare represented by Formula (II-A):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, and wherein:    -   X is optionally substituted imidazolyl, triazolyl, 3-pyridinyl        or 4-pyridinyl;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl. C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl; cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl; or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR₇₁R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂        ⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR^(7l)R⁸¹ substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷—SO₂NR⁷¹R⁸¹        or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkyl, —SO₂NR⁷³R⁸³ or —NR⁷²R⁸³ substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,        -alkenylaryl, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-,        -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is        optionally substituted with one or more independent halo, cyano,        hydroxy, nitro, R⁶⁸, C₁₋₁₀alkoxy, —COOR⁷⁴, —(C═O)N(R⁷⁴)—,        —NR⁷⁴CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —SO₂NR⁷⁴R⁷⁵, or        —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₁₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —OR⁷⁷,        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —N⁷⁷R⁸⁷ substituents; or        mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or        —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with        R^(5a), or R^(4b) with R^(5b), or R^(4c) with R^(5C), taken        together with the respective carbon atom to which they are        attached, form a carbonyl or 3-10 membered saturated or        unsaturated monocyclic or polycyclic ring, wherein said ring is        optionally substituted with R⁶⁹; or R^(4a) with R^(5a), or        R^(4b) with R^(5b), or R^(4c) with R^(5c), taken together with        the respective carbon atom to which they are attached, form a        3-10 membered saturated or unsaturated monoheterocyclic or        polyheterocyclic ring, wherein said ring is optionally        substituted with R⁶⁹;    -   R^(6a), R^(6b), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently        hydrogen, halo, —OR⁷⁷—SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸,        —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally,        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or        aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl; haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or        mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or        —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl) (C₀₋₄alkyl)        substituents; and    -   n1, n2, n3, n5 and n7 are each independently equal to 0, 1 or 2.

In another embodiment, a compound is represented by Formula (I), or an Eor Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof; wherein Yis —NR^(6b)CO—, and the other variables are as described above.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (III):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, and wherein:    -   X is an unsaturated heterocycle selected from pyrrolyl,        pyrazolyl, imidazolyl triazolyl, benzimidazolyl, benzotriazolyl,        tetrazolyl, thiazole, 3-pyridinyl or 4-pyridinyl, any of which        is substituted with one or more independent R⁶⁶ substituents;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl C₀₋₁₀alkyl heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷,        —SO₂NR⁷¹R⁸¹ or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -alkenylaryl-,        -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-,        -alkenylhetaryl-, or -aryl-, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, R⁶⁸, C₁₋₁₀alkoxy, —COOR⁷⁴, —(C═O)N(R⁷⁴)—, —NR⁷⁴CONR⁷⁴R⁷⁵,        —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or —NR⁷⁶R⁸⁶        substituents;    -   Q¹ is C₀₋₆alkyl, cycloC₃₋₈alkyl, bridged bicycloalkyl, —OR⁷⁵,        —COR⁷⁴, —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), —CO₂R⁷⁵, —CONR⁷⁵R⁸⁵, —(C═S)OR⁷⁵,        —(C═O)SR⁷⁵, —NO₂, —CN, halo, —S(O)_(n6)R⁷⁵, —SO₂NR⁷⁵R⁸⁵,        —NR⁷⁵(C═NR⁷⁷⁵)NR⁷⁷⁷⁵R⁸⁵, —NR⁷⁵(C═NR⁷⁷⁵)OR⁷⁷⁷⁵,        —NR⁷⁵(C═NR⁷⁷⁵)SR⁷⁷⁷⁵, —O(C═O)OR⁷⁵, —O(C═O)NR⁷⁵R⁸⁵, —O(C═O)SR⁷⁵,        —S(C═O)OR⁷⁵, —S(C═O)NR⁷⁵R⁸⁵, —S(C═O)SR⁷⁵, —NR⁷⁵(C═O)NR⁷⁷⁵R⁸⁵, or        —NR⁷⁵(C═S)NR⁷⁷⁵R⁸⁵; in the case of —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), R⁷⁵ and        R⁸⁵ taken together with the nitrogen atom to which they are        attached form a 3-10 membered heterocyclic saturated ring, or        heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl. C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        Which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents;        or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or        R^(4b) with R^(5b), or R^(4c) with R^(5C), taken together with        the respective carbon atom to which they are attached, form a        carbonyl or 3-10 membered saturated or unsaturated monocyclic or        polycyclic ring, wherein said ring is optionally substituted        with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b), or        R^(4c) with R^(5c), taken together with the respective carbon        atom to which they are attached, form a 3-10 membered saturated        or unsaturated monoheterocyclic or polyheterocyclic ring,        wherein said ring is optionally substituted with R⁶⁹;    -   R^(6a), R^(6b), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently        hydrogen, halo, —OR⁷⁷, —SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸,        —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl, any of Which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or        aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₁₀alkyl,        di(C₁₋₆-alkyl)aminoC₁₋₁₀alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₁₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        heterocycyl-C₀₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl,        C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆alkylaminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl) (C₀₋₄alkyl) substituents; and    -   n1, n2, n3, n4, n5, n6, and n7 are each independently equal to        0, 1 or 2.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (III-A):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, and wherein:    -   X is optionally substituted imidazolyl, triazolyl, 3-pyridinyl        or 4-pyridinyl;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkylcarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷,        —SO₂NR⁷¹R⁸¹ or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,        -alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-,        -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is        optionally substituted with one or more independent halo, cyano,        hydroxy, nitro, R⁶⁸, C₁₋₁₀alkoxy, —COOR⁷⁴, —(C═O)N(R⁷⁴)—,        —NR⁷⁴CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or        —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents;        or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or        R^(4b) with R^(5b), or R^(4c) with R^(5c), taken together with        the respective carbon atom to which they are attached, form a        carbonyl or 3-10 membered saturated or unsaturated monocyclic or        polycyclic ring, wherein said ring is optionally substituted        with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b), or        R^(4c) with R^(5c), taken together with the respective carbon        atom to which they are attached, form a 3-10 membered saturated        or unsaturated monoheterocyclic or polyheterocyclic ring,        wherein said ring is optionally substituted with R⁶⁹;    -   R^(6a), R^(6b), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently        hydrogen, halo, —OR⁷⁷, —SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸,        —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)NR⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally,        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or        aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R8⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)        (C₀₋₄alkyl) substituents; aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₂₋₁₀alkenyl, C₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀ alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; and    -   n1, n2, n3, n5, and n7 are each independently equal to 0, 1 or        7.

In another embodiment, a compound is represented by Formula (I), or an Eor Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof, wherein Yis oxygen, and the other variables are as described above.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (IV):

-   -   or an F or Z isomer thereof, syn or anti isomer thereof, an        optically pure iso thereof, or pharmaceutically acceptable salt        thereof, and wherein;    -   X is an unsaturated heterocycle selected from pyrrolyl,        pyrazolyl, imidazolyl, triazolyl, benzimidazolyl,        benzotriazolyl, tetrazolyl, thiazole, 3-pyridinyl or        4-pyridinyl, any of which is optionally substituted with one or        more independent R⁶⁶ substituents;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆-aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents, or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷,        —SO₂NR⁷¹R⁸¹ or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -hetaryl-,        -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-,        -alkenylhetaryl-, or -aryl-, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, R⁶⁸, C₁₋₁₀alkyl, —COOR⁷⁴, —(C═O)N(R⁷⁴)—, —NR⁷⁴CONR⁷⁴R⁷⁵,        —NR⁷⁴COOR⁷⁵, SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or —NR⁷⁶R⁸⁶        substituents;    -   Q¹ is C₀₋₆alkyl, cycloC₃₋₈alkyl, bridged bicycloalkyl, —OR⁷⁵,        —COR⁷⁴, —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), —CO₂R⁷⁵, —CONR⁷⁵R⁸⁵, —(C═S)OR⁷⁵,        —(C═O)SR⁷⁵, —NO₂, —CN, halo, —S(O)_(n6)R⁷⁵, —SO₂NR⁷⁵R⁸⁵,        —NR⁷⁵(C═NR⁷⁷⁵)NR⁷⁷⁵R⁸⁵, —NR⁷⁵(C═NR⁷⁷⁵)OR⁷⁷⁷⁵,        —NR⁷⁵(C═NR⁷⁷⁵)SR⁷⁷⁷⁵, —O(C═O)OR⁷⁵, —O(C═O)NR⁷⁵R⁸⁵, —O(C═O)SR⁷⁵,        —S(C═O)OR⁷⁵, —S(C═O)NR⁷⁵R⁸⁵, —S(C═O)SR⁷⁵, —NR⁷⁵(C═O)NR⁷⁷⁵R⁸⁵, or        —NR⁷⁵(C═S)NR⁷⁷⁵R⁸⁵; in the case of —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), R⁷⁵ and        R⁸⁵ taken together with the nitrogen atom to which they are        attached form a 3-10 membered heterocyclic saturated ring, or        heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxy C₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents;        or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl or hetaryl-C₂₋₁₀alkynyl, any of Which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₁₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or        R^(4b) with R^(5b), or R^(4c) with R^(5C), taken together with        the respective carbon atom to which they are attached, form a        carbonyl or 3-10 membered saturated or unsaturated monocyclic or        polycyclic ring, wherein said ring is optionally substituted        with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b), or        R^(4c) with R^(5c), taken together with the respective carbon        atom to which they are attached, form a 3-10 membered saturated        or unsaturated monoheterocyclic or polyheterocyclic ring,        wherein said ring is optionally substituted with R⁶⁹;    -   R^(6a), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently hydrogen,        halo, —OR⁷⁷, —SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂,        —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or        aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl,        —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or        —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₁₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocycyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)        (C₀₋₄alkyl) substituents; aryl C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₂₋₁₀alkenyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₁₀alkenyl, haloC₂₋₁₀alkynyl,        —COOH, C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; and    -   n1, n2, n3, n4, n5, n6, and n7 are each independently equal to        0, 1 or 2,

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (IV-A):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically e isomer thereof, or pharmaceutically acceptable salt        thereof, and wherein;    -   X is optionally substituted imidazolyl, triazolyl, 3-pyridinyl        or 4-pyridinyl;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆-aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷,        —SO₂NR⁷¹R⁸¹ or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —S⁷², —N⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,        -alkenylaryl , -hetaryl-, -hetarylalkyl-, -alkylhetaryl-,        -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is        optionally substituted with one or more independent halo, cyano,        hydroxy, nitro, R⁶⁸, C₁₋₁₀alkoxy, —COOR⁷⁴, —(C═O)N(R⁷⁴)—,        —NR⁷⁴CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or        —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents;        or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; with R^(5a), or R^(4b)        with R^(5b), or R^(4c) with R^(5C), taken together with the        respective carbon atom to which they are attached, form a        carbonyl or 3-10 membered saturated or unsaturated monocyclic or        polycyclic ring, wherein said ring is optionally substituted        with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b), or        R^(4c) with R^(5c), taken together with the respective carbon        atom to which they are attached, form a 3-10 membered saturated        or unsaturated monoheterocyclic or polyheterocyclic ring,        wherein said ring is optionally substituted with R⁶⁹;    -   R^(6a), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently hydrogen,        halo, —O⁷⁷, —SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂,        —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀ alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₀₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₁₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl) (C₀₋₄alkyl)        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; and    -   n1, n2, n3, n5, and n7 are each independently equal to 0, 1 or        2.

In another embodiment, a compound is represented by Formula (I), or an Eor Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof, wherein Yis aryl or heteroaryl, and the other variables are as described above.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (V):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, wherein:    -   X is an unsaturated heterocycle selected from pyrrolyl,        pyrazolyl, imidazolyl, triazolyl, benzimidazolyl,        benzotriazolyl, tetrazolyl, thiazole, 3-pyridinyl or        4-pyridinyl, any of which is optionally substituted with one or        more independent less substituents;    -   R¹ is hydrogen, C₀₋₆alkyl, —OR⁷, —SR⁷, or —NR⁷R⁸;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or more independent        C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷¹R⁸¹ or —CONR⁷¹R⁸¹        substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —N⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R⁹)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   B is aryl or heteroaryl which is optionally substituted with one        or more independent halo, —OR⁷⁷—SR⁷⁷, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7),        —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸,        C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl; or aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,        -alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-,        -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is        optionally substituted with one or more independent halo, cyano,        hydroxy, nitro, R⁶⁸, C₁₋₁₀alkyl, —COOR⁷⁴, —(C═O)N(R⁷⁴)—,        —NR⁷⁴CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or        —NR⁷⁶R⁸⁶ substituents;    -   Q¹ is C₀₋₆alkyl, cycloC₃₋₈alkyl, bridged bicycloalkyl, —OR⁷⁵,        —COR⁷⁴, —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), —CO₂R⁷⁵, —CONR⁷⁵R⁸⁵, —(C═S)OR⁷⁵,        —(C═O)SR⁷⁵, —NO₂, —CN, halo, —S(O)_(n6)R⁷⁵, —SO₂NR⁷⁵R⁸⁵,        —NR⁷⁵(C═NR⁷⁷⁵)NR⁷⁷⁷⁵R⁸⁵, —NR⁷⁵(C═NR⁷⁷⁵)OR⁷⁷⁷⁵,        —NR⁷⁵(C═NR⁷⁷⁵)SR⁷⁷⁷⁵, —O(C═O)OR⁷⁵, —O(C═O)NR⁷⁵R⁸⁵, —O(C═O)SR⁷⁵,        —S(C═O)OR⁷⁵, —S(C═O)NR⁷⁵R⁸⁵, —S(C═O)SR⁷⁵, —NR⁷⁵(C═O)NR⁷⁷⁵R⁸⁵, or        —NR⁷⁵(C═S)NR⁷⁷⁵R⁸⁵; in the case of —NR⁷⁵R⁸⁵(R⁹⁵)_(n6), R⁷⁵ and        R⁸⁵ taken together with the nitrogen atom to which they are        attached form a 3-10 membered heterocyclic saturated ring, or        heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶ substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —OR⁷⁷,        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or        mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or        —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with        R^(5a), or R^(4b) with R^(5b), or R^(4c) with R^(5C), taken        together with the respective carbon atom to which they are        attached, form a carbonyl or 3-10 membered saturated or        unsaturated monocyclic or polycyclic ring, wherein said ring is        optionally substituted with R⁶⁹; or R^(4a) with R^(5a), or        R^(4b) with R^(5b), or R^(4c) with R^(5c), taken together with        the respective carbon atom to which they are attached, form a        3-10 membered saturated or unsaturated monoheterocyclic or        polyheterocyclic ring, wherein said ring is optionally        substituted with R⁶⁹;    -   R^(6a), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently hydrogen,        halo, —OR⁷⁷, —SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂,        —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₀₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl)        or —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; aryl C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkenyl, C₂₋₁₀alkynyl, halo C₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or        mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or        —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; and    -   n1, n2, n3, n4, n5, no, and n7 are each independently equal to        0, 1 or 2.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (V-A):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, wherein:    -   X is optionally substituted imidazolyl, triazolyl,        benzimidazolyl, benzotriazolyl, 3-pyridinyl or 4-pyridinyl;    -   R¹ is hydrogen, C₀₋₆alkyl, —OR⁷, —SR⁷, or —NR⁷R⁸;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₁₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆-aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷,        —SO₂NR⁷¹R⁸¹ or —CONR⁷¹R⁸¹ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   B is aryl or heteroaryl which is optionally substituted with one        or more independent halo, —OR⁷⁷—SR⁷⁷, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7),        —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸,        C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or        heterocyclyl-C₂₋₁₀alkynyl; or aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸—SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents;    -   Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,        -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-,        -alkenylhetaryl-, or -aryl-, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, R⁶⁸, C₁₋₁₀alkyl, —COOR⁷⁴, —(C═O)N(R⁷⁴)—, —NR⁷⁴CONR⁷⁴R⁷⁵,        —NR⁷⁴COOR⁷⁵, —SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or —NR⁷⁶R⁸⁶        substituents;    -   R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are each        independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents;        or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkynyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷,        —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or        R^(4b) with R^(5b), or R^(4c) with R^(5C), taken together with        the respective carbon atom to which they are attached, form a        carbonyl or 3-10 membered saturated or unsaturated monocyclic or        polycyclic ring, wherein said ring is optionally substituted        with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b), or        R^(4c) with R^(5c), taken together with the respective carbon        atom to which they are attached, form a 3-10 membered saturated        or unsaturated monoheterocyclic or polyheterocyclic ring,        wherein said ring is optionally substituted with R⁶⁹;    -   R^(6a), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently hydrogen,        halo, —OR⁷⁷, —SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂,        —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₀₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸,        R⁸, R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and        R⁹⁸ are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or        mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or        —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl) (C₀₋₄alkyl)        substituents; and    -   n1, n2, n3, n5, and n7 are each independently equal to 0, 1 or        2.

In another embodiment, a compound is represented by Formula (I), or an Eor Z isomer thereof, syn or anti isomer thereof, an optically pureisomer thereof, or pharmaceutically acceptable salt thereof, wherein Yis as described below and the other variables are as described above.

In another embodiment, compounds useful for the purposes describedherein are represented by Formula (VI):

-   -   or an E or Z isomer thereof, syn or anti isomer thereof, an        optically pure isomer thereof, or pharmaceutically acceptable        salt thereof, wherein:    -   X is optionally substituted imidazolyl, triazolyl,        benzimidazolyl, benzotriazolyl 3-pyridinyl or 4-pyridinyl;    -   R¹ is hydrogen, C₀₋₆alkyl, —OR⁷, —SR⁷, or —NR⁷R⁸;    -   R² and R³ are each independently hydrogen, C₀₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,        C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,        C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,        C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,        cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,        cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,        heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,        heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl,        C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,        C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,        diC₁₋₆-aminocarbonyl, mono(aryl)aminocarbonyl,        di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of        which is optionally substituted with one or more independent        halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷¹R⁸¹, or        —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷¹, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl —CONR⁷¹R⁸¹,        —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹        substituents;    -   or R² and R³ taken together with the carbon atom to which they        are attached form a 3-10 membered saturated ring, unsaturated        ring, heterocyclic saturated ring, or heterocyclic unsaturated        ring, wherein said ring is optionally substituted with one or        more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷,        —SO₂NR⁷¹R⁸¹ or —CONR⁷¹R⁸¹ substituents;    -   Y is hydrogen, halogen, —OR⁷⁴, —SR⁷⁴, —R⁷⁴, —C(═NR⁷⁴)NR⁷⁵R⁷⁶,        —CN, —C(═NR⁷⁴)OR⁷⁵—, —COR⁷⁴, —R⁷⁴COR⁷⁵, —CR⁷⁴R⁷⁵COR⁷⁶, —COOR⁷⁴,        —R⁷⁴COOR⁷⁵, —CR⁷⁴R⁷⁵COOR⁷⁶, —CONR⁷⁴R⁷⁵, —CR⁷⁴R⁷⁵CONR⁷⁴R⁷⁵,        —NR⁷⁴COOR⁷⁵, —NR⁷⁴COR⁷⁵, —NR⁷⁴CONR⁷⁵R⁷⁶, —SO₂CR⁷⁴R⁷⁵,        —SO₂NR⁷⁴R⁷⁵, —NR⁷⁴SO₂NR⁷⁵R⁷⁶, —NR⁷⁴R⁷⁵, aryl or heteroaryl, any        of which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl haloC₂₋₁₀alkynyl,        —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or        —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —OR⁷²,        —SR⁷², —NR⁷²R⁸²(R⁹)_(n5), or G¹ and R³ taken together with the        carbon atom to which they are attached form a 3-10 membered        saturated ring, unsaturated ring, heterocyclic saturated ring,        or heterocyclic unsaturated ring, any of which is optionally        substituted with one or more independent R and an N heteroatom        of the heterocyclic saturated ring or heterocyclic unsaturated        ring optionally is substituted with an R⁷² substituent; or in        the case of —NR⁷²R⁸²(R)_(n5), R⁷² and R⁸² taken together with        the nitrogen atom to which they are attached form a 3-10        membered heterocyclic saturated ring, or heterocyclic        unsaturated ring, wherein said ring is optionally substituted        with one or more independent halo, cyano, hydroxy, nitro,        C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents;    -   R^(6a), R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are each independently hydrogen,        halo, —OR⁷⁷, —SH, —NR⁷⁷R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂,        —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₂₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₀₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or        aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with        one or more independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸        substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,        di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of        which is optionally substituted with one or more independent        halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,        haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,        —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of        —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), R⁷⁸ and R⁸⁸ taken together with the nitrogen        atom to which they are attached form a 3-10 membered mono or        polycyclic saturated ring, mono or polycyclic unsaturated ring,        wherein said ring is optionally substituted with one or more        independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,        —SO₂R⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;    -   R⁷, R⁷¹, R⁷², R⁷³R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸, R⁸,        R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and R⁹⁸        are each independently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,        C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,        C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,        cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,        cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,        cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,        heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl,        C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl, C₂₋₁₀alkynylcarbonyl,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,        monoC₁₋₆aminocarbonyl, diC₁₋₆alkylaminocarbonyl,        mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or        C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally        substituted with one or more independent halo, cyano, hydroxy,        nitro, C₁₋₁₀alkyl, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is        optionally substituted with one or more independent halo, cyano,        nitro, —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; or hetaryl-C₀₋₄alkyl, hetaryl-C₂₋₁₀alkenyl, or        hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted        with one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,        haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,        —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or        —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or        mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or        —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally        substituted with one or more independent halo, cyano, nitro,        —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,        C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₄alkyl),        —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or —N(C₀₋₄alkyl)(C₀₋₄alkyl)        substituents; and    -   n5 and n7 are each independently equal to 0, 1 or 2.

The compounds of the present invention include compounds represented byFormula (I) above, or a pharmaceutically acceptable salt thereof, and

1) wherein X is hetaryl, imidazolyl, triazolyl, benzimidazolyl,benzotriazolyl, 3-pyridinyl or 4-pyridinyl, any of which is optionallysubstituted with one or more independent R⁶⁶ substituents; or

2) wherein X is imidazolyl or triazolyl; or

3) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents,and Q¹ is —CO₂H or —CO₂R⁷⁵; or

4) wherein Y is nitrogen; or

5) wherein Y is nitrogen; and X is hetaryl, imidazolyl triazolyl,3-pyridinyl or 4-pyridinyl, any of which is optionally substituted withone or more independent R⁶⁶ substituents; or

6) wherein Y is nitrogen; and X is imidazolyl, or triazolyl; or

7) wherein Y is nitrogen; and X is imidazolyl, or triazolyl; n2 is 0;and Q¹ is —CO₂H or —CO₂R⁷⁵; or

8) wherein Y is nitrogen; and X is imidazolyl, or triazolyl; n3 is 0;and Q¹ is —CO₂H or —CO₂R⁷⁵; or

9) wherein Y is nitrogen; and X is imidazolyl, or triazolyl; n1 and n3are 0; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

10) wherein Y is —NHCO—; or

11) wherein Y is —NHCO—; and X is hetaryl, imidazolyl, triazolyl,3-pyridinyl or 4-pyridinyl, any of which is optionally substituted withone or more independent R⁶⁶ substituents; or

12) wherein Y is —NHCO—; and X is imidazolyl, or triazolyl; or

13) wherein Y is —NHCO—; and X is imidazolyl, or triazolyl; n2 and n3are 0; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

14) wherein Y is —NHCO—; and X is imidazolyl, or triazolyl; n3, n2 andn4 are 0; or

15) wherein Y is —NHCO—; and X is imidazolyl, or triazolyl; n2 is 0; andQ¹ is —CO₂H or —CO₂R⁷⁵; or

16) wherein Y is —NHCO—; and X is imidazolyl, or triazolyl; n3 is 0; andQ¹ is —CO₂H or —CO₂R⁷⁵; or

17) wherein Y is oxygen; or

18) wherein Y is oxygen; and X is hetaryl, imidazolyl, triazolyl,3-pyridinyl or 4-pyridinyl, any of which is optionally substituted withone or more independent R⁶⁶ substituents; or

19) wherein Y is oxygen; and X is imidazolyl, or triazolyl; or

20) wherein Y is oxygen; and X is imidazolyl, or triazolyl; n1 and n3are 0; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

21) wherein Y is optionally substituted aryl or heteroaryl; or

22) wherein Y is optionally substituted phenyl; or

23) wherein Y is optionally substituted phenyl and X is hetaryl,imidazolyl, triazolyl, benzimidazolyl, benzotriazolyl, 3-pyridinyl or4-pyridinyl, any of which is optionally substituted with one or moreindependent R⁶⁶ substituents; or

24) wherein Y is optionally substituted phenyl and X is imidazolyl ortriazolyl; or

25) wherein Y is phenyl substituted with halogen or CF₃; and X isimidazolyl or triazolyl; or

26) wherein Y is phenyl substituted with halogen or CF; and X isimidazolyl or triazolyl; n1, n2 and n3 are 0; and Q¹ is —CO₂H or—CO₂R⁷⁵; or

27) wherein Y is phenyl substituted with halogen or CF₃; and X isimidazolyl or triazolyl; n1, n2 and n3 are 0; G¹ is hydrogen; and Q¹ is—CO₂H or —CO₂R⁷⁵; or

28) wherein Y is phenyl and X is imidazolyl or triazolyl; n1, n2 and n3are 0; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

29) wherein Y is phenyl and X is imidazolyl or triazolyl; n1, n2 and n3are 0; G¹ is hydrogen; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

30) wherein Y is phenyl and X is imidazolyl or triazolyl; n2 and n3 are0; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

31) wherein Y is phenyl and X is imidazolyl or triazolyl; n2 and n3 are0; G¹ is hydrogen; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

32) wherein Y is phenyl and X is 3-pyridin) or 4-pyridinyl; n2 and n3are 0; G¹ is hydrogen; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

33) wherein Y is phenyl and X is 3-pyridinyl or 4-pyridinyl; n2 and n3are 0; G¹ is hydrogen; G¹ is hydrogen; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

34) wherein Y is phenyl and X is imidazolyl or triazolyl; n1 and n2 are0; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

35) wherein Y is phenyl and X is imidazolyl or triazolyl; n1 and n2 are0; G¹ is hydrogen; and Q¹ is —CO₂H or —CO₂R⁷⁵; or

36) wherein Y is phenyl and X is imidazolyl or triazolyl; n2 and n3 are0; and Q¹ is tetrazole; or

37) wherein Y is phenyl and X is imidazolyl or triazolyl; n1 and n2 are0; and Q¹ is tetrazole; or

38) where in Y is hydrogen; or

39) where in Y is a halogen; or

40) where in Y is chlorine or bromine; or

41) where in Y is R⁷⁴; or

42) where in Y is OR⁷⁴; or

43) where in Y is SR⁷⁴; or

44) where in Y is NH₂; or

45) where in Y is CONH2; or

46) where in Y is COOR⁷⁶; or

47) where in Y is COOH; or

48) where in Y is COR⁷⁶; or

49) where in Y is COCF₃; or

50) where in Y is —NHCOR⁷⁶; or

51) where in Y is NR⁷⁵R⁷⁶CONR⁷⁵R⁷⁶; or

52) where in Y is NHCONH2; or

53) where in Y is CN; or

54) where in Y is —C(═NR⁷⁴)NR⁷⁵R⁷⁶; or,

55) where in Y is NR⁷⁵R⁷⁶SONR⁷⁵R⁷⁶; or

56) where in Y is NR⁷⁵R⁷⁶SO₂NR⁷⁵R⁷⁶; or

57) where in Y is SO₂NR⁷⁵R⁷⁶; or

58) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹and R³ taken together with the carbon atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally substituted with one or more independent R⁶⁷ and an Nheteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is NH; Q¹ is C₀₋₆alkyl, —CO₂R or CONR⁷⁵R⁸⁵; R^(4b) andR^(5b) are each independently C₀₋₆alkyl, or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached forma 3-10 membered saturated ring; R^(4a) and R^(5a) are each independentlya C₀₋₁₀alkyl, any of which is optionally substituted with one or moreindependent halo, cyano, nitro, —OR⁷⁷, —SO2NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷substituents; or R^(4a) with R⁵, wherein said ring is optionallysubstituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached forma 3-10 membered saturated or unsaturated heterocyclic ring, wherein saidring is optionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n)7R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀ alkyl; and Q¹ is —CO₂CH₃or —CO₂iPr; or

59) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; Y is NH or NHCO; Q¹ isC₀₋₆alkyl, CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵; R^(4a), R^(4b), R^(5a), and R^(5b) areeach independently a C₀₋₁₀alkyl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —OR⁷⁷—SONR⁷⁷R⁸⁷ or—NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or R^(4b) with R^(5b)taken together with the respective carbon atom to which they areattached, form a 3-10 membered saturated or unsaturated ring, whereinsaid ring is optionally substituted with R⁶⁹; or R^(4a) with R^(5a), orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached form a 3-10 membered saturated or unsaturatedheterocyclic ring, wherein said ring is optionally substituted with R⁶⁹;and R^(6a) and R^(6b) each independently halo, —OR⁷⁸,—NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁵, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸,—SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀alkyl; and G¹ is di(C₁₋₆alkyl)amino; or

60) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹and R³ taken together with the carbon atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally substituted with one or more independent R⁶⁷ and an Nheteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SONR⁷³R⁸³ or —NR⁷³R⁸³ substituents;Y is NH or NHCO; Q¹ is C₀₋₆alkyl, —CO₂R or —CONR⁷⁵R⁸⁵; R^(4b) and R^(5b)are each independently C₀₋₆alkyl, or R^(4b) with R^(5b) taken togetherwith the respective carbon atom to which they are attached form a 3-10membered saturated ring; R^(4a) and R^(5a) are each independently aC₀₋₁₀alkyl, any of which is optionally substituted with one or moreindependent halo, cyano, nitro, —OR⁷⁷, —SO2NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷substituents; or R^(4a) with R⁵, wherein said ring is optionallysubstituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached forma 3-10 membered saturated or unsaturated heterocyclic ring, wherein saidring is optionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n)7R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀ alkyl; and R^(4b) andR^(5b) are both ethyl or are both methyl or are independently ethyl ormethyl; or

61) wherein X is hetaryl, imidazolyl, or triazolyl any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹and R³ taken together with the carbon atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally, substituted with one or more independent R⁶⁷ and an Nheteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is NH or NHCO; Q¹ is C₀₋₆alkyl, —CO₂R or —CONR⁷⁵R⁸⁵;R^(4b) and R^(5b) are each independently C₀₋₆alkyl, or R^(4b) withR^(5b) taken together with the respective carbon atom to which they areattached form a 3-10 membered saturated ring; R^(4a) and R^(5a) are eachindependently a C₀₋₁₀alkyl, any of which is optionally substituted withone or more independent halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or—NR⁷⁷R⁸⁷ substituents; or R^(4a) with R⁵, wherein said ring isoptionally substituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) withR^(5b) taken together with the respective carbon atom to which they areattached form a 3-10 membered saturated or unsaturated heterocyclicring, wherein said ring is optionally substituted with R⁶⁹; and R^(6a)and R^(6b) are each independently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7),—CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n)7R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀alkyl; and Q¹ is —CO₂H; or

62) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹and R³ taken together with the carbon atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally, substituted with one or more independent R⁶⁷ and an Nheteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is NHCO; Q¹ is C₀₋₆alkyl, —CO₂R or —CONR⁷⁵R⁸⁵; R^(4b)and R^(5b) are each independently C₀₋₆alkyl, or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached forma 3-10 membered saturated ring; R^(4a) and R^(5a) are each independentlya C₀₋₁₀alkyl, any of which is optionally substituted with one or moreindependent halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷substituents; or R^(4a) with R⁵, wherein said ring is optionallysubstituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached forma 3-10 membered saturated or unsaturated heterocyclic ring, wherein saidring is optionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CONR⁷⁸R⁸⁸, —NO₂, —CN,—S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀ alkyl; and R^(4a) with R^(5a) takentogether with the respective carbon atom to which they are attached forma cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring; or

63) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹and R³ taken together with the carbon atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally substituted with one or more independent R⁶⁷ and an Nheteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is oxygen; Q¹ is C₃₋₆alkyl, —CO₂R or —CONR⁷⁵R⁸⁵; R^(4b)and R^(5b) are each independently C₀₋₆alkyl, or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached forma 3-10 membered saturated ring; R^(4a) and R^(5a) are each independentlya C₀₋₁₀alkyl, any of which is optionally substituted with one or moreindependent halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷substituents; or R^(4a) with R⁵, wherein said ring is optionallysubstituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached forma 3-10 membered saturated or unsaturated heterocyclic ring, wherein saidring is optionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀ alkyl; and Q¹ is —CO₂H;or

64) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; Y is oxygen; Q¹ isC₀₋₆alkyl, CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵; R^(4a), R^(4b), R^(5a), and R^(5b) areeach independently a C₀₋₁₀alkyl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —OR⁷⁷—SO₂NR⁷⁷R⁸⁷ or—NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or R^(4b) with R^(5b)taken together with the respective carbon atom to which they areattached, form a 3-10 membered saturated or unsaturated ring, whereinsaid ring is optionally substituted with R⁶⁹; or R^(4a) with R^(5a), orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached form a 3-10 membered saturated or unsaturatedheterocyclic ring, wherein said ring is optionally substituted with R⁶⁹;and R^(6a) and R^(6b) are each independently halo, —OR⁷⁸,—NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO_, —CN, —S(O)_(n7)R⁷⁸,—SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀alkyl; and G¹ is di(C₁₋₆alkyl)amino; or

65) wherein X is hetaryl, imidazolyl, triazolyl, 3-pyridinyl or4-pyridinyl, any of which is optionally substituted with one or moreindependent R⁶⁶ substituents; R¹, R² and R³ are each independentlyhydrogen or C₀₋₁₀ alkyl; G¹ is —NR⁷²R⁸²; or G¹ and R³ taken togetherwith the carbon atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent R⁶⁷ and an N heteroatom of theheterocyclic saturated ring or heterocyclic unsaturated ring optionallyis substituted with an R⁷² substituent; or R⁷² and R⁸² taken togetherwith the nitrogen atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is optionallysubstituted phenyl; Q¹ is C₀₋₆alkyl, —CO₂SO₂R⁷⁵, or —CONR⁷⁴R⁸⁵; R^(4a),R^(4b), R^(5a), and R^(5b) are each independently a C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a)with R^(5a), or with R^(5b) taken together with the respective carbonatom to which they are attached, form a 3-10 membered saturated orunsaturated ring, wherein said ring is optionally substituted with R⁶⁹;or R^(4a) with R^(5a) or R^(4b) with R^(5b) taken together with therespective carbon atom to which they are attached form a 3-10 memberedsaturated or unsaturated heterocyclic ring, wherein said ring isoptionally substituted with R⁶⁹; and R^(6a) and R^(6b) eachindependently halo, —OR⁷⁸, CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸,—SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀alkyl; or

66) wherein X is imidazolyl or triazolyl; R¹ is hydrogen, R² and R³ areeach independently C₀₋₁₀alkyl G¹ is —NR⁷²R⁸²; or G¹ and R³ takentogether with the carbon MOM to which they are attached form a 3-10membered saturated ring, unsaturated ring, heterocyclic saturated ring,or heterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent R⁶⁷ and an. N heteroatom of theheterocyclic saturated ring or heterocyclic unsaturated ring optionallyis substituted with an R⁷² substituent; or R⁷² and R⁸² taken togetherwith the nitrogen atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is optionallysubstituted phenyl; Q¹ is —CO₂R⁷⁵ or —CONR⁷⁵R⁸⁵; R^(4a), R^(4b), R^(5a)and R^(5b) each independently a C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, cyano, nitro, —OR⁷⁷, —SO₂or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or R^(4b) with R^(5b)taken together with the respective carbon atom to which they areattached, form a 3-10 membered saturated or unsaturated ring, whereinsaid ring is optionally substituted with R⁶⁹; R^(4a) with R^(5a), orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached form a 3-10 membered saturated or unsaturatedheterocyclic ring, wherein said ring is optionally substituted with R⁶⁹,and R^(6a) and R^(6b) each hydrogen; or

67) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹and R³ taken together with the carbon atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally substituted with one or more independent R⁶⁷ and an Nheteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is optionally substituted phenyl; Q¹ is C₀₋₆alkyl, —CO₂Ror —CONR⁷⁵R⁸⁵; R^(4a) and R^(5a) are each hydrogen; or R^(4b) and R^(5b)are each independently a C₀₋₁₀alkyl, any of which is optionallysubstituted with R⁶⁹; or R^(4b) with R^(5b) taken together with therespective carbon atom to which they are attached form a 3-10 memberedsaturated or unsaturated ring, wherein said ring is optionallysubstituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached forma 3-10 membered saturated or unsaturated heterocyclic ring, wherein saidring is optionally substituted with R⁶⁹; or

68) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹and R³ taken together with the carbon atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally substituted with one or more independent R⁶⁷ and an Nheteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is optionally substituted phenyl; Q¹ is C₀₋₆alkyl, —CO₂Ror —CONR⁷⁵R⁸⁵; R^(4b) and R^(5b) are each independently C₀₋₆alkyl, orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached form a 3-10 membered saturated ring; R^(4a) andR^(5b) are each independently a C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, cyano, nitro, —OR⁷⁷,—SO2NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R⁵, wherein saidring is optionally substituted with R⁶⁹; or R^(4a) with R^(5a), orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached form a 3-10 membered saturated or unsaturatedheterocyclic ring, wherein said ring is optionally substituted with R⁶⁹;and R^(6a) and R^(6b) are each independently halo, —OR⁷⁸,—NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n)7R⁷⁸,—SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀ alkyl; or

69) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹and R³ taken together with the carbon atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally substituted with one or more independent R⁶⁷ and an Nheteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is optionally substituted phenyl; Q¹ is C₀₋₆alkyl, —CO₂Ror —CONR⁷⁵R⁸⁵; R^(4b) and R^(5b) are each independently C₀₋₆alkyl, orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached form a 3-10 membered saturated ring; R^(4a) andR^(5a) are each independently a C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, cyano, nitro, —OR⁷⁷,—SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R⁵, wherein saidring is optionally substituted with R⁶⁹; or R^(4a) with R^(5a), orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached form a 3-10 membered saturated or unsaturatedheterocyclic ring, wherein said ring is optionally substituted with R⁶⁹;and R^(6a) and R^(6b) are each independently halo, —OR⁷⁸,—NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n)7R⁷⁸,—SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀ alkyl; and Q¹ is —CO₂H; or

70) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; Y is optionallysubstituted phenyl; Q¹ is C₀₋₆alkyl, CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵; R^(4a),R^(4b), R^(5a) and R^(5b) are each independently a C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷—SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) withR^(5a), or R^(4b) with R^(5b) taken together with the respective carbonatom to which they are attached, form a 3-10 membered saturated orunsaturated ring, wherein said ring is optionally substituted with —R⁶⁹;or R^(4a) with R^(5a), or R^(4b) with —R^(5b) taken together with therespective carbon atom to which they are attached form a 3-10 memberedsaturated or unsaturated heterocyclic ring, wherein said ring isoptionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀alkyl; and G¹ isdi(C₁₋₆alkyl)amino; or

71) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; Y is optionallysubstituted phenyl; Q¹ is C₀₋₆alkyl, CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵, R^(4a),R^(4b), R^(5a), and R^(5b) are each independently a C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷—SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) withR^(5a), or R^(4b) with R^(5b) taken together with the respective carbonatom to which they are attached, form a 3-10 membered saturated orunsaturated ring, wherein said ring is optionally substituted with R⁶⁹;or R^(4a) with R^(5a), or R^(4b) with R^(5b) taken together with therespective carbon atom to which they are attached form a 3-10 memberedsaturated or unsaturated heterocyclic ring, wherein said ring isoptionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀alkyl; and G¹ isdi(C₁₋₆alkyl)amino, dimethylamino, ethylmethylamino, diethylamino, orisopropylmethylamino; or

72) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents;R¹, R² and R³ are each independently C₀₋₁₀alkyl; Y is optionallysubstituted phenyl; Q¹ is C₀₋₆alkyl, CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵; R^(4a),R^(4b), R^(5a), and R^(5b) are each independently a C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷—SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) withR^(5a), or R^(4b) with R^(5b) taken together with the respective carbonatom to which they are attached, form a 3-10 membered saturated orunsaturated ring, wherein said ring is optionally substituted with R⁶⁹;or R^(4a) with R^(5a), or R^(4b) with R^(5b) taken together with therespective carbon atom to which they are attached form a 3-10 memberedsaturated or unsaturated heterocyclic ring, wherein said ring isoptionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂ ⁷⁸NR⁸⁸; or C₀₋₁₀alkyl; and G¹ isheterocycle, pyrrolidine; or

73) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents; R¹is C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹ and R³ taken together with thecarbon atom to which they are attached form a 3-10 membered saturatedring, unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent R⁶⁷ and an N heteroatom of the heterocyclicsaturated ring or heterocyclic unsaturated ring optionally issubstituted with an R⁷² substituent; or R⁷² and R⁸² taken together withthe nitrogen atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is optionallysubstituted phenyl; Q¹ is C₀₋₆alkyl, —CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵, R^(4a),R^(4b), R^(5a), and R^(5b) are each independently a C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a)with R^(5a), or R^(4a) with R^(5b) taken together with the respectivecarbon atom to which they are attached, form a 3-10 membered saturatedor unsaturated ring, wherein said ring is optionally substituted withR⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) taken together withthe respective carbon atom to which they are attached form a 3-10membered saturated or unsaturated heterocyclic ring, wherein said ringis optionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n7)R⁷⁸, —S(O)₂R⁷⁸R⁸⁸, or C₀₋₁₀alkyl; and R² and R³ areeach independently hydrogen, methyl, or ethyl; or

74) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents; R¹is C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹ and R³ taken together with thecarbon atom to which they are attached form a 3-10 membered saturatedring, unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent R⁶⁷ and an N heteroatom of the heterocyclicsaturated ring or heterocyclic unsaturated ring optionally issubstituted with an substituent; or R⁷² and R⁸² taken together with thenitrogen atom to which they are attached form a 3-10 membered saturatedring, unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,—SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is optionally substitutedphenyl; Q¹ is C₀₋₆alkyl, —CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵; R^(4a), R^(4b), R^(5a),and R^(5b) are each independently a C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, cyano, nitro,—OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached, form a 3-10 membered saturated or unsaturatedring, wherein said ring is optionally substituted with R⁶⁹; or R^(4a)with R^(5a), or R^(4b) with R^(5b) taken together with the respectivecarbon atom to which they are attached form a 3-10 membered saturated orunsaturated heterocyclic ring, wherein said ring is optionallysubstituted with R⁶⁹; R^(6a) and R^(6b) are each independently halo,—OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN,—S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀alkyl, R² is hydrogen; and G¹ and R³taken together with the carbon atom to which they are attached form

wherein •, is the carbon to which they are attached;or G¹ and R³ taken together with the carbon atom to which they areattached form

wherein • is the carbon to which they are attached, any of which isoptionally substituted by 1-10 independent R⁶⁷ substituents; or

75) wherein X is imidazole; or

76) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents; R¹is C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹ and R³ taken together with thecarbon atom to which they are attached form a 3-10 membered saturatedring, unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent R⁶³ and an N heteroatom of the heterocyclicsaturated ring or heterocyclic unsaturated ring optionally issubstituted with an R⁷² substituent; or R⁷² and R⁸² taken together withthe nitrogen atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is optionallysubstituted phenyl; Q¹ is C₀₋₆alkyl, —CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵; R^(4a),R^(4b), R^(5a), and R^(5b) are each independently a C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a)with R^(5a), or R^(4b) with R^(5b) taken together with the respectivecarbon atom to which they are attached, form a 3-10 membered saturatedor unsaturated ring, wherein said ring is optionally substituted withR⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) taken together withthe respective carbon atom to which they are attached form a 3-10membered saturated or unsaturated heterocyclic ring, wherein said ringis optionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, or C₀₋₁₀alkyl; and R² is hydrogenand R³ is methyl; or

77) wherein X is hetaryl, imidazolyl, or triazolyl, any of which isoptionally) substituted with one or more independent R66 substituents;R¹ is C₀₋₁₀alkyl; G¹ is —NR⁷²R⁸²; or G¹ and R³ taken together with thecarbon atom to which they are attached form a 3-10 membered saturatedring, unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent R⁶³ and an N heteroatom of the heterocyclicsaturated ring or heterocyclic unsaturated ring optionally issubstituted with an R⁷² substituent; or R⁷² and R⁸² taken together withthe nitrogen atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is optionallysubstituted phenyl; Q¹ is C₀₋₆alkyl, —CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵; R^(4a),R^(4b), R^(5a); and R^(5b) are each independently a C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a)with R^(5a) or R^(4b) with R^(5b) taken together with the respectivecarbon atom to which they are attached, form a 3-10 membered saturatedor unsaturated ring, wherein said ring is optionally substituted withR⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) taken together withthe respective carbon atom to which they are attached form a 3-10membered saturated or unsaturated heterocyclic ring, wherein said ringis optionally substituted with R⁶⁹; and R^(6a) and R^(6b) are eachindependently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7), —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸ or C₀₋₁₀alkyl; and R² is hydrogenand R³ is ethyl; or

78) wherein X is hetaryl, imidazolyl, triazolyl, 3-pyridinyl or4-pyridinyl, any of which is optionally substituted with one or moreindependent R⁶⁶ substituents; R¹ is C₀₋₁₀alkyl; G¹ is hydrogen or—NR⁷²R⁸²; or G¹ and R³ taken together with the carbon atom to which theyare attached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent R⁶³ andan N heteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is optionally substituted phenyl; Q¹ is C₀₋₆alkyl,—CO₂R⁷⁵, or —CONR⁷⁵R⁸⁵, R^(4a), R^(4b), R^(5a), and R^(5b) are eachindependently a C₀₋₁₀alkyl, any of which is optionally substituted withone or more independent halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or—NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a) or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached,form a 3-10 membered saturated or unsaturated ring, wherein said ring isoptionally substituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) withR^(5b) taken together with the respective carbon atom to which they areattached form a 3-10 membered saturated or unsaturated heterocyclicring, wherein said ring is optionally substituted with R⁶⁹; and R^(6a)and R^(6b) are each independently halo, —OR⁷⁸, —NR⁷⁸R⁸⁸(R⁹⁸)_(n7),—CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, orC₀₋₁₀alkyl; and R² and R³ are independently methyl, ethyl or isopropyl;or

79) wherein X is imidazolyl or triazolyl; R¹ is hydrogen; G¹ is—NR⁷²R⁸²; or G¹ and R³ taken together with the carbon atom to which theyare attached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent R⁶⁷ andan N heteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² together with the nitrogen atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally substituted with one or more independent halo, cyano,hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y isoptionally substituted phenyl; Q¹ is —CO₂R⁷⁵ or —CONR⁷⁵R⁸⁵; R^(4a),R^(4b), R^(5a), and R^(5b) are each independently a C₀₋₁₀alkyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a)with R^(5a), or R^(4b) with R^(5b) taken together with the respectivecarbon atom to which they are attached, form a 3-10 membered saturatedor unsaturated ring, wherein said ring is optionally substituted withR⁶⁹; or R^(4a) with R^(5a), or R^(4b) with R^(5b) taken together withthe respective carbon atom to which they are attached form a 3-10membered saturated or unsaturated heterocyclic ring, wherein said ringis optionally substituted with R⁶⁹; and R^(6a) is hydrogen; R² ishydrogen; and R³ is methyl; or

80) wherein X is imidazolyl, triazolyl, 3-pyridinyl or 4-pyridinyl; R¹is hydrogen; G¹ is —NR⁷²R⁸²; or G¹ and R³ taken together with the carbonatom to which they are attached form a 3-10 membered saturated ring,unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent R⁶⁷ and an N heteroatom of the heterocyclicsaturated ring or heterocyclic unsaturated ring optionally issubstituted with an R⁷² substituent; or R⁷² and R⁸² taken together withthe nitrogen atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is optionallysubstituted phenyl; Q¹ is —CO₂R⁷⁵ or —CONR⁷⁵R⁸⁵; R^(4a), R^(4b), R^(5a),and R^(5b) each independently a C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, cyano, nitro, —OR⁷⁷,—SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or R^(4b)with R^(5b) taken together with the respective carbon atom to which theyare attached, form a 3-10 membered saturated or unsaturated ring,wherein said ring is optionally substituted with R⁶⁹; or R^(4a) withR^(5a), or R^(4b) with R^(5b) taken together with the respective carbonatom to which they are attached form a 3-10 membered saturated orunsaturated heterocyclic ring, wherein said ring is optionallysubstituted with R⁶⁹; and R^(6a) is hydrogen; R² is hydrogen; and R³ isethyl; or

81) wherein X is imidazolyl, triazolyl, 3-pyridinyl or 4-pyridinyl; R¹is hydrogen; G¹ is —NR⁷²R⁸²; or G¹ and R³ taken together with the carbonatom to which they are attached form a 3-10 membered saturated ring,unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent R⁶⁷ and an N heteroatom of the heterocyclicsaturated ring or heterocyclic unsaturated ring optionally issubstituted with an R⁷² substituent; or R⁷² and R⁸² taken together withthe nitrogen atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is hydrogen,halogen, —OR⁷⁴, —SR⁷⁴, —R⁷⁴, —C(═NR⁷⁴)NR⁷⁵R⁷⁶, —CN, —C(—NR⁷⁴)OR⁷⁵—,—COR⁷⁴, —R⁷⁴COR⁷⁵, —CR⁷⁴R⁷⁵COR⁷⁶, —COOR⁷⁴, —R⁷⁴COOR⁷⁵, —CR⁷⁴R⁷⁵COOR⁷⁶,—CONR⁷⁴R⁷⁵, —CR⁷⁴R⁷⁵CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —NR⁷⁴COR⁷⁵, —NR⁷⁴CONR⁷⁵R⁷⁶,—SO₂CR⁷⁴R⁷⁵, —SO₂NR⁷⁴R⁷⁵, —NR⁷⁴SO₂NR⁷⁵R⁷⁶, —NR⁷⁴R⁷⁵, aryl or heteroaryl;and R^(6a) is hydrogen; and R² and R³ are independently methyl, ethyl orisopropyl; G¹ is heterocycle, pyrrolidine; or

82) wherein X is imidazolyl, triazolyl, 3-pyridinyl or 4-pyridinyl; R¹is hydrogen; G¹ is hydrogen; or G¹ and R³ taken together with the carbonatom to which they are attached form a 3-10 membered saturated ring,unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent R⁶⁷ an N heteroatom of the heterocyclic saturatedring or heterocyclic unsaturated ring optionally is substituted with anR⁷² substituent; or R⁷² and R⁸² taken together with the nitrogen atom towhich they are attached form a 3-10 membered saturated ring, unsaturatedring, heterocyclic saturated ring, or heterocyclic unsaturated ring,wherein said ring is optionally substituted with one or more independenthalo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is hydrogen, halogen, —OR⁷⁴, —SR⁷⁴, —R⁷⁴,—C(═NR⁷⁴)NR⁷⁵R⁷⁶, —CN, —C(═NR⁷⁴)OR⁷⁵—, —COR⁷⁴, —R⁷⁴COR⁷⁵, —CR⁷⁴R⁷⁵COR⁷⁶,—COOR⁷⁴, —R⁷⁴COOR⁷⁵, —CR⁷⁴R⁷⁵COOR⁷⁶, —CONR⁷⁴R⁷⁵, —CR⁷⁴R⁷⁵CONR⁷⁴R⁷⁵,—NR⁷⁴COOR⁷⁵, —NR⁷⁴COR⁷⁵, —NR⁷⁴CONR⁷⁵R⁷⁶, —SO₂CR⁷⁴R⁷⁵, —SO₂NR⁷⁴R⁷⁵,—NR⁷⁴SO₂NR⁷⁵R⁷⁶, —NR⁷⁴R⁷⁵, an or heteroaryl; and R^(6a) is hydrogen; andR² and R³ are independently methyl, ethyl or isopropyl; or

83) wherein X is imidazolyl, triazolyl, 3-pyridinyl or 4-pyridinyl; R¹is hydrogen; G¹ is hydrogen; or G¹ and R³ taken together with the carbonatom to which they are attached form a 3-10 membered saturated ring,unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent R⁶⁷ and an N heteroatom of the heterocyclicsaturated ring or heterocyclic unsaturated ring optionally issubstituted with an R⁷² substituent; or R⁷² and R⁸² taken together withthe nitrogen atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is optionallysubstituted phenyl; Q¹ is —CO₂R⁷⁵ or —CONR⁷⁵R⁸⁵; R^(4a), R^(4b), R^(5a),and R^(5b) are each independently a C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, cyano, nitro,—OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), orR^(4b) with R^(5b) taken together with the respective carbon atom towhich they are attached, form a 3-10 membered saturated or unsaturatedring, wherein said ring is optionally substituted with R⁶⁹; or R^(4a)with R^(5a), or R^(4b) with R^(5b) taken together with the respectivecarbon atom to which they are attached form a 3-10 membered saturated orunsaturated heterocyclic ring, wherein said ring is optionallysubstituted with R⁶⁹; and R^(6a) is hydrogen; and R² and R³ areindependently methyl, ethyl or isopropyl; or

84) wherein X is imidazolyl or triazolyl; R¹ is hydrogen; G¹ is—NR⁷²R⁸², or G¹ and R³ taken together with the carbon atom to which theyare attached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent R⁶⁷ andan N heteroatom of the heterocyclic saturated ring or heterocyclicunsaturated ring optionally is substituted with an R⁷² substituent; orR⁷² and R⁸² taken together with the nitrogen atom to which they areattached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷³R⁸³ or —NR⁷³R⁸³substituents; Y is optionally substituted phenyl; Q¹ is —CO₂R⁷⁵ or—CONR⁷⁵R⁸⁵; R^(4a), R^(4b), R^(5a), and R^(5b) are each independently aC₀₋₁₀alkyl, any of which is optionally substituted with one or moreindependent halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷substituents; or R^(4a) with R^(5a), or R^(4b) with R^(5b) takentogether with the respective carbon atom to which they are attached,form a 3-10 membered saturated or unsaturated ring, wherein said ring isoptionally substituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) withR^(5b) taken together with the respective carbon atom to which they areattached form a 3-10 membered saturated or unsaturated heterocyclicring, wherein said ring is optionally substituted with R⁶⁹; and R^(6a)is hydrogen; and R² and R³ are independently methyl, ethyl or isopropyl;and wherein, in each case, the other variables are as defined above forFormula (I).

It will be appreciated that each of the compounds described herein andeach of the classes and subclasses of compounds described above (I-VI)may be substituted as described generally herein, or may be substitutedaccording to any one or more of the subclasses described above andherein.

Some of the foregoing compounds can comprise one or more asymmetriccenters, and thus can exist in various isomeric forms, e.g.,stereoisomers and/or diastereomers. Thus, inventive compounds andpharmaceutical compositions thereof may be in the form of an individualenantiomer, diastereomer or geometric isomer, or may be in the form of amixture of stereoisomers. In certain embodiments, the compounds of theinvention are enantiopure compounds. In certain other embodiments,mixtures of stereoisomers or diastereomers are provided.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the Z or E isomer, unlessotherwise indicated. The invention additionally encompasses thecompounds as individual isomers substantially free of other isomers andalternatively, as mixtures of various isomers, e.g., racemic mixtures ofstereoisomers. In addition to the above-mentioned compounds per se, thisinvention also encompasses pharmaceutically acceptable derivatives ofthese compounds and compositions comprising one or more compounds of theinvention and one or more pharmaceutically acceptable excipients oradditives.

Compounds of the invention may be prepared by crystallization ofcompound of formula (I)-(VI) under different conditions and may exist asone or a combination of polymorphs of compound of general formula(I)-(VI) forming part of this invention. For example, differentpolymorphs may be identified and/or prepared using different solvents,or different mixtures of solvents for recrystallization; by performingcrystallizations at different temperatures; or by using various modes ofcooling, ranging from very fast to very slow cooling duringcrystallizations. Polymorphs may also be obtained by heating or meltingthe compound followed by gradual or fast cooling. The presence ofpolymorphs may be determined by solid probe NMR spectroscopy, IRspectroscopy, differential scanning calorimetry, powder X-raydiffractogram and/or other techniques. Thus, the present inventionencompasses inventive compounds, their derivatives, their tautomeric andgeometrical isomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts their pharmaceutically acceptablesolvates and pharmaceutically acceptable compositions containing them.Tautomeric forms of compounds of the present invention include,pyrazoles, pyridones and enols, etc., and geometrical isomers includeE/Z isomers of compounds having double bonds and cis-trans isomers ofmonocyclic or fused ring systems, etc.,

Pharmaceutical Compositions

In practice, the compounds represented by Formulas (I)-(VI), orpharmaceutically acceptable salts thereof, of this invention can becombined as the active ingredient in intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration. e.g.,oral or parenteral (including intravenous). Thus, the pharmaceuticalcompositions of the present invention can be presented as discrete unitssuitable for oral administration such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion, or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound represented by Formulas (I)-(VI), or a pharmaceuticallyacceptable salt thereof, may also be administered by controlled releasemeans and/or delivery devices. The compositions may be prepared by anyof the methods of pharmacy. In general, such methods include a step ofbringing into association the active ingredient with the carrier thatconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, The product can then be conveniently shaped into the desiredpresentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formulas (I)-(VI). The compounds of Formulas(I)-(VI), or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents, and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient.

For example, a formulation intended for the oral administration tohumans may contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water, A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula (I) of this invention, or a pharmaceutically acceptable saltthereof, via conventional processing methods. As an example, a cream orointment is prepared by admixing hydrophilic material and water,together with about 5 wt % to about 10 wt % of the compound, to producea cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula (I)-(VI), or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

Generally, dosage levels on the order of from about 0.01 mg/kg to about1 50 mg/kg of body weight per day are useful in the treatment of theabove indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, dermatological diseases and cancersmay be effectively treated by the administration of from about 0.01 to50 mg of the compound per kilogram of body weight per day, oralternatively about 0.5 mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

As discussed above this invention provides novel compounds that havebiological properties useful for the treatment of any of a number ofconditions or diseases in which inhibition of CYP or the activitiesthereof have a therapeutically useful role. Further description ofpharmaceutical compositions is provided herein below.

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, which comprise any one or more of thecompounds described herein (or a prodrug, pharmaceutically acceptablesalt or other pharmaceutically acceptable derivative thereof), andoptionally comprise a pharmaceutically acceptable carrier. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents. Alternatively, a compound of thisinvention may be administered to a patient in need thereof incombination with the administration of one or more other therapeuticagents. For example, additional therapeutic agents for conjointadministration or inclusion in a pharmaceutical composition with acompound of this invention may be an approved agent to treat the same orrelated indication, or it may be any one of a number of agentsundergoing approval in the Food and Drug Administration that ultimatelyobtain approval for the treatment of any disorder related to fibrosis.It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,hut is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or a pro-drug or other adduct or derivative of acompound of this invention which upon administration to a patient inneed is capable of providing, directly or indirectly, a compound asotherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts Which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts of amines, carboxylic acids, and other types ofcompounds, are well known in the art. For example, S. M. Berge, et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein byreference. The salts can be prepared in situ during the final isolationand purification of the compounds of the invention, or separately byreacting a free base or free acid function with a suitable reagent, asdescribed generally below. For example, a free base function can bereacted with a suitable acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may, include metal salts such as alkali metal salts, e.g.sodium or potassium salts; and alkaline earth metal salts, e.g. calciumor magnesium salts. Examples of pharmaceutically acceptable, nontoxicacid addition salts are salts of an amino group formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid or with organic acids such as aceticacid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid or malonic acid or by using other methods used in the art such asion exchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike, Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

Additionally, as used herein, the term “pharmaceutically acceptableester” refers to esters that hydrolyze in vivo and include those thatbreak down readily in the human body to leave the parent compound or asalt thereof. Suitable ester groups include, for example, those derivedfrom pharmaceutically acceptable aliphatic carboxylic acids,particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, inwhich each alkyl or alkenyl moiety advantageously has not more than 6carbon atoms. Examples of particular esters include formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

Furthermore, the term “pharmaceutically acceptable prodrugs” as usedherein refers to those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the issues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” refers tocompounds that are rapidly transformed in vivo to yield the parentcompound of the above formula, for example by hydrolysis in blood, orN-demethylation of a compound of the invention where R¹ is methyl. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference. By way of example, N-methylatedpro-drugs of the compounds of the invention are embraced herein.

As described above, the pharmaceutical compositions of the presentinvention additionally comprise a pharmaceutically acceptable carrier,which, as used herein, includes any and all solvents, diluents, or otherliquid vehicle, dispersion or suspension aids, surface active agents,isotonic agents, thickening or emulsifying agents, preservatives, solidbinders, lubricants and the like, as suited to the particular dosageform desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutical compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutical composition, its use is contemplatedto be within the scope of this invention. Some examples of materialswhich can serve as pharmaceutically acceptable carriers include, but arenot limited to, sugars such as lactose, glucose and sucrose; starchessuch as corn starch and potato starch; cellulose and its derivativessuch as sodium carboxymethyl cellulose, ethyl cellulose and celluloseacetate; powdered tragacanth; malt; gelatine; talc; excipients such ascocoa butter and suppository waxes; oils such as peanut oil, cottonseedoil; safflower oil, sesame oil; olive oil; corn oil and soybean oil;glycols; such as propylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut (peanut), corn, germ, olive, castor, and sesameoils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols andfatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

In one embodiment, liquid compositions or liquid formulations comprisingcompounds of the invention are provided that have increased solubilityas compared to compounds of the invention dissolved in aqueous buffersuch as phosphate-buffered saline. In one embodiment, such liquidcompositions with increased solubility are provided by a compositioncomprising polyethylene glycol, polysorbate or a combination thereof. Inone embodiment, the polyethylene glycol is polyethylene glycol 300. Inanother embodiment the polysorbate is polysorbate 80. In anotherembodiment the polyethylene glycol is present at about 40% to about 60%(v/v). In another embodiment the polysorbate is present at about 5% toabout 15% (v/v). In another embodiment the polyethylene glycol ispresent at about 50% (v/v). In another embodiment the polysorbate ispresent at about 10% (v/v). In one formulation, the polyethylene glycolis present at 50% (v/v) together with polysorbate 80 at 10% (v/v). Thebalance of the solution can be a saline solution, a buffer or a bufferedsaline solution, such as phosphate-buffered saline. The pH of thesolution can be from about pH 5 to about pH 9, and in other embodiments,about from pH 6 to about pH 8. In one embodiment the pH of the buffer is7.4. In the foregoing embodiments, the compound of the invention issoluble at a concentration higher than in buffer alone, and can bepresent at about 0.8 to about 10 milligrams per milliliter of solution,or even higher. These formulations offer the preparation of convenientdosing solutions of practical volumes for single dose administration, byany route, in particular a parenteral route. In one embodiment, theroute is intravenous, subcutaneous or intraperitoneal. Such compositionswith a higher solubility permit achievement of more elevated bloodconcentrations that provide efficacy when the threshold Cmax (maximalblood concentration after administration) should be achieved for optimalefficacy.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension orcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionthat, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents

Solid compositions of a similar type may also be employed as fillers insoil and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

In other embodiments, solid dosage forms of compounds embodied hereinare provided, in some embodiment, such solid dosage forms have improvedoral bioavailability. In one embodiment, a formulation is prepared in asolid formulation comprising about 20% (w/w) compound of the invention,about 10-20% (w/w) GLUCIRE® 44/14, about 10-20% (w/w) vitamin Esuccinate (TPS), 0 to about 60% polyethylene glycol 400, 0 to about 40%Lubrizol 0 to about 15% Cremophor RH 40 (w/w), and about 1% (w/w) BHT.Formulations containing Cremophor RH 20 are liquid at room temperaturebut waxy solids at 4 C. The foregoing examples of one or more agents toaid in preparing formulations of inventive compound are merelyillustrative and non-limiting.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose and starch. Such dosage forms may alsocomprise, as in normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such asmagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

In other embodiments solid dosage forms are provided. In certainembodiments, such solid dosage forms provide a higher than about a 20%oral bioavailability. As will be shown in the examples below, compoundsof the invention can be co-precipitated with one or more agents such asmannitol, a combination of mannitol and lactobionic acid, a combinationof mannitol and gluconic acid, a combination of mannitol andmethanesulfonic acid, a combination of microcrystalline cellulose andoleic acid or a combination of pregelatinized starch and oleic acid. Theforegoing examples of one or more agents to aid in preparingformulations of inventive compound are merely illustrative andnon-limiting. Non-limiting examples of inventive compounds in such soliddosage forms include

The present invention encompasses pharmaceutically acceptable topicalformulations of inventive compounds. The term “pharmaceuticallyacceptable topical formulation”, as used herein, means any formulationwhich is pharmaceutically acceptable for intradermal administration of acompound of the invention by application of the formulation to theepidermis. In certain embodiments of the invention, the topicalformulation comprises a carrier system. Pharmaceutically effectivecarriers include, but are not limited to, solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, plasters, liposomes,powders, emulsions, microemulsions, and buffered solutions (e.g.,hypotonic or buffered saline) or any other carrier known in the art fortopically administering pharmaceuticals. A more complete listing ofart-known carriers is provided by reference texts that are standard inthe art, for example, Remington's Pharmaceutical Sciences, 16th Edition,1980 and 17th Edition, 1985, both published by Mack Publishing Company,Easton, Pa., the disclosures of which are incorporated herein byreference in their entireties. In certain other embodiments, the topicalformulations of the invention may comprise excipients, Anypharmaceutically acceptable excipient known in the art may be used toprepare the inventive pharmaceutically acceptable topical formulations.Examples of excipients that can be included in the topical formulationsof the invention include, but are not limited to, preservatives,antioxidants, moisturizers, emollients, buffering agents, solubilizingagents, other penetration agents, skin protectants, surfactants, andpropellants, and/or additional therapeutic agents used in combination tothe inventive compound. Suitable preservatives include, but are notlimited to, alcohols, quaternary amines, organic acids, parabens, andphenols. Suitable antioxidants include, but are not limited to, ascorbicacid and its esters, sodium bisulfite, butylated hydroxytoluene,butylated hydroxyanisole, tocopherols, and chelating agents like EDTAand citric acid. Suitable moisturizers include, but are not limited to,glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol.Suitable buffering agents for use with the invention include, but arenot limited to, citric, hydrochloric, and lactic acid buffers. Suitablesolubilizing agents include, but are not limited to, quaternary ammoniumchlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.Suitable skin protectants that can be used in the topical formulationsof the invention include, but are not limited to, vitamin E oil,allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

In certain embodiments, the pharmaceutically acceptable topicalformulations of the invention comprise at least a compound of theinvention and a penetration enhancing agent. The choice of topicalformulation will depend or several factors, including the condition tobe treated, the physicochemical characteristics of the inventivecompound and other excipients present, their stability in theformulation, available manufacturing equipment, and costs constraints.As used herein the term “penetration enhancing agent” means an agentcapable of transporting a pharmacologically active compound through thestratum corneum and into the epidermis or dermis, preferably, withlittle or no systemic absorption. A wide variety of compounds have beenevaluated as to their effectiveness in enhancing the rate of penetrationof drugs through the skin. See, for example, Percutaneous PenetrationEnhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., BocaRaton, Fla. (1995), which surveys the use and testing of various skinpenetration enhancers, and Buyuktimkin et al., Chemical Means ofTransdermal Drug Permeation Enhancement in Transdermal and Topical DrugDelivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.),Interpharm Press Inc., Buffalo Grove, Ill. (1997). In certain exemplaryembodiments, penetration agents for use with the invention include, butare not limited to, triglycerides (e.g., soybean oil), aloe compositions(e.g., aloe-vera gel), ethyl alcohol, isopropyl alcohol,octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400,propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g.,isopropyl myristate, methyl laurate, glycerol monooleate, and propyleneglycol monooleate) and N-methylpyrrolidone.

In certain embodiments, the compositions may be in the form ofointments, pastes, creams, lotions, gels, powders, solutions, sprays,inhalants or patches. In certain exemplary embodiments, formulations ofthe compositions according to the invention are creams, which mayfurther contain saturated or unsaturated fatty acids such as stearicacid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl,alcohols, stearic acid being particularly preferred. Creams of theinvention may also contain a non-ionic surfactant, for example,polyoxy-40-stearate. In certain embodiments, the active component isadmixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Formulations for intraocularadministration are also included. Additionally, the present inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are made by dissolving or dispensing the compound inthe proper medium. As discussed above, penetration enhancing agents canalso be used to increase the flux of the compound across the skin. Therate can be controlled by either providing a rate controlling membraneor by dispersing the compound in a polymer matrix or gel.

It will also be appreciated that the compounds and pharmaceuticalcompositions of the present invention can be formulated and employed incombination therapies, that is, the compounds and pharmaceuticalcompositions can be formulated with or administered concurrently with,prior to, or subsequent to, one or more other desired therapeutics ormedical procedures. The particular combination of therapies(therapeutics or procedures) to employ in a combination regimen willtake into account compatibility of the desired therapeutics and/orprocedures and the desired therapeutic effect to be achieved. It willalso be appreciated that the therapies employed may achieve a desiredeffect for the same disorder (for example, an inventive compound may beadministered concurrently with another anti-inflammatory agent), or theymay achieve different effects (e.g., control of any adverse effects). Innon-limiting examples, one or more compounds of the invention may beformulated with at least one cytokine, growth factor or otherbiological, such as an interferon, e.g., alpha interferon, or with atleast another small molecule compound. Non-limiting examples ofpharmaceutical agents that may be combined therapeutically withcompounds of the invention include: antivirals and antifibrotics such asinterferon alpha, combination of interferon alpha and ribavirin,Lamivudine, Adefovir dipivoxil and interferon gamma; anticoagulants suchas heparin and warfarin; antiplatelets e.g., aspirin, ticlopidine andclopidogrel; other growth factors involved in regeneration, e.g., VEGFand FGF and mimetics of these growth factors; antiapoptotic agents; andmotility and morphogenic agents.

In certain embodiments, the pharmaceutical compositions of the presentinvention further comprise one or more additional therapeutically activeingredients (e.g., anti-inflammatory and/or palliative). For purposes ofthe invention, the term “Palliative” refers to treatment that is focusedon the relief of symptoms of a disease and/or side effects of atherapeutic regimen, but is not curative. For example, palliativetreatment encompasses painkillers, antinausea medications andanti-sickness drugs.

3) Research Uses, Clinical Uses, Pharmaceutical Uses and Methods ofTreatment

In another embodiment, the aforementioned Formulae (I)-(VI) andcompounds have anti-fibrotic activities and thus are useful for theprevention, treatment or lessening of the severity of a condition ordisease associated with or characterized by increased, excessive orinappropriate fibrosis. Such conditions and diseases include but are notlimited to fibrotic liver disease, hepatic ischemia-reperfusion injury,cerebral infarction, pancreatic fibrosis, ischemic heart disease,neurodegenarative disease, renal disease or lung (pulmonary) fibrosis.In certain embodiments, the method is for treating or lessening theseverity of a disease or condition selected from liver fibrosisassociated with hepatitis C, hepatitis B, delta hepatitis, chronicalcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions(stones in the bile duct), cholangiopathies (primary biliary cirrhosisand sclerosing cholangitis), autoimmune liver disease, and inheritedmetabolic disorders (Wilson's disease, hemochromatosis, and alpha-1antitrypsin deficiency); damaged and/or ischemic organs, transplants orgrafts; ischemia/reperfusion injury; stroke; cerebrovascular disease;myocardial ischemia; atherosclerosis; renal failure; renal fibrosis oridiopathic pulmonary fibrosis. In certain exemplary embodiments, themethod is for the treatment of wounds for acceleration of healing;vascularization of a damaged and/or ischemic organ, transplant or graft;amelioration of ischemia/reperfusion injury in the brain, heart, liver,kidney, and other tissues and organs; normalization of myocardialperfusion as a consequence of chronic cardiac ischemia or myocardialinfarction; development or augmentation of collateral vessel developmentafter vascular occlusion or to ischemic tissues or organs; fibroticdiseases; hepatic disease including fibrosis and cirrhosis; lungfibrosis; radiocontrast nephropathy; fibrosis secondary to renalobstruction; renal trauma and transplantation; renal failure secondaryto chronic diabetes and/or hypertension; amytrophic lateral sclerosis,muscular dystrophy, pancreatitis, scleroderma, chronic obstructivepulmonary disease, emphysema, diabetes mellitus, multiple sclerosis,trauma to the central nervous system, and hereditary neurodegenerativedisorders including the leukodystrophies such as metachromaticleukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe'sdisease, phenylketonuria, Canavan disease, Pelizaeus-Merzbacher diseaseand Alexander's disease.

Furthermore, compounds of the invention are also useful for thetreatment, of various skin diseases, such as actinic keratoses, arsenickeratoses, inflammatory and non-inflammatory acne, psoriasis,ichthyoses, keratinization and hyperproliferative disorders of the skin,eczema, atopic dermatitis, Darriers disease, lichen planus; forpreventing, treating, and reversal of glucocorticoid, age, and photodamage to the skin.

In another embodiment, compounds of the invention, typically but notlimited to compounds of Formula (VI), are also useful for prevention andtreatment of cancerous and precancerous conditions, including, forexample, premalignant and malignant hyperproliferative diseases such ascancers of the breast, skin, prostate, colon, bladder, cervix, uterus,stomach, lung, esophagus, blood and lymphatic system, larynx, oralcavity, metaplasias, dysplasias, neoplasias, leukoplakias and papillomasof the mucous membranes, and in the treatment of Kaposi's sarcoma. Inone embodiment, prevention or treatment of cancer of the prostate, andcastration-resistant prostate cancer, are uses of the compounds embodiedherein. In addition, inventive compounds can also be used as agents totreat diseases of the eye, including, for example, proliferativevitreoretinopathy, retinal detachment, corneopathies such as dry eye, aswell as in the treatment and prevention of various cardiovasculardiseases, including, without limitation, diseases associated with lipidmetabolism such as dyslipidemias, prevention of post-angioplastyrestenosis and as an agent to increase the level of circulation tissueplasminogen activator. Other uses include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts, various inflammatory diseases such as pulmonaryfibrosis, ileitis, colitis and Krohn's disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease and stroke,improper pituitary function, including insufficient production of growthhormone, modulation of apoptosis, including both the induction ofapoptosis, restoration of hair growth, including combination therapieswith the present compounds and other agents such as minoxidil, diseasesassociated with the immune systems, including use of the presentcompounds as immunosuppressant and immunostimulants, modulation of organtransplant rejection and facilitation of wound healing, includingmodulation of chelosis. Compounds are also useful in treating type IInon-insulin dependent diabetes mellitus (NIDDM).

With regard to treatment and prevention of dysproliferative disorders,inventive compounds are useful in other cases where abnormal orexcessive cellular proliferation is the cause of pathology, such as indysproliferative diseases including cancer, inflammatory joint and skindiseases such as rheumatoid arthritis, and neovascularization in the eyeas a consequence of diabetic retinopathy, suppression of cellularproliferation is a desired goal in the treatment of these and otherconditions. In either case, therapy to promote or suppress proliferationmay be beneficial locally but not systemically, and for a particularduration, and proliferation-modulating therapies must be appropriatelyapplied. Compounds of the invention are beneficial for the treatment ofcancer and other dysproliferative diseases and conditions.

Conditions and diseases amenable to prophylaxis or treatment with thecompounds of the invention include but are not limited to those in whichabnormal vascular or cellular proliferation occurs. Such conditions anddiseases include as in dysproliferative diseases including cancer andpsoriasis, various inflammatory diseases characterized by proliferationof cells such as atherosclerosis and rheumatoid arthritis, andneovascularization in the eye as a consequence of diabetic retinopathy,suppression of cellular proliferation is a desired goal in the treatmentof these and other conditions. As certain of the compounds of theinvention have been found to possess antiproliferative activity oncells, as well as antiangiogenic activity, both activities may bebeneficial in the treatment of, for example, solid tumors, in which boththe dysproliferative cells and the enhanced tumor vasculature elicitedthereby are targets for inhibition by the agents of the invention. Ineither case, therapy to promote or suppress proliferation may bebeneficial locally but not systemically, and for a particular duration,and proliferation-modulating therapies must be appropriately applied.The invention embraces localized delivery of such compounds to theaffected tissues and organs, to achieve a particular effect.

Non-limiting examples of cancers, tumors, malignancies, neoplasms, andother dysproliferative diseases that can be treated according to theinvention include leukemias such as myeloid and lymphocytic leukemias,lymphomas, myeloproliferative diseases, and solid tumors, such as butnot limited to sarcomas and carcinomas such as fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, andretinoblastoma.

The present invention is also directed to treatment of non-malignanttumors and other disorders involving inappropriate cell or tissue growthby administering a therapeutically effective amount of an agent of theinvention. For example, it is contemplated that the invention is usefulfor the treatment of arteriovenous (AV) malformations, particularly inintracranial sites. The invention may also be used to treat psoriasis, adermatologic condition that is characterized by inflammation andvascular proliferation; benign prostatic hypertrophy, a conditionassociated with inflammation and possibly vascular proliferation; andcutaneous fungal infections. Treatment of other hyperproliferativedisorders is also contemplated. The agents may also be used topically toremove warts, birthmarks, moles, nevi, skin tags, lipomas, angiomasincluding hemangiomas, and other cutaneous lesions for cosmetic or otherpurposes.

As noted above, other uses of the compounds herein include intentionalablation or destruction of tissues or organs in a human or animal, forexample, in the area of animal husbandry, and in the field ofreproductive biology, to reduce the number of developing embryos; as anabortifacient, and as a means to achieve a biochemical castration,particularly for livestock and domesticated animals such as pets.

As mentioned above, vascularization of the vitreous humor of the eye asa consequence of diabetic retinopathy is a major cause of blindness, andinhibition of such vascularization is desirable. Other conditions inwhich vascularization is undesirable include certain chronicinflammatory diseases, in particular inflammatory joint and skindisease, but also other inflammatory diseases in which a proliferativeresponse occurs and is responsible for part of all of the pathology. Forexample, psoriasis is a common inflammatory skin disease characterizedby prominent epidermal hyperplasia and neovascularization in the dermalpapillae. Proliferation of smooth muscle cells, perhaps as a consequenceof growth factors, is a factor in the narrowing and occlusion of themacrovasculature in atherosclerosis, responsible for myocardialischemia, angina, myocardial infarction, and stroke, to name a fewexamples. Peripheral vascular disease and arteriosclerosis obliteranscomprise an inflammatory component.

Moreover, localized ablation of tissues or even organs usingantiproliferative or antiangiogenic compounds as characterized hereinmay find use in treatment of certain central nervous system diseases orconditions which otherwise may require dangerous invasive procedures;removal of cosmetically undesirable cutaneous lesions are furthertargets for the antiproliferative agents of the invention. Inreproductive biology, such antiproliferative agents may be used asabortifacients or for non-surgical castration, particularly for use inlivestock and domesticated animals. These are also merely illustrativeof the uses of the instant agents.

Furthermore, inhibition of CYP17 reduces androgens, such astestosterone, levels, and thus compounds embodied herein, in particularbut no limited to compounds of Formula (VI), are useful for preventionor treatment of any condition or disease in which reducing androgenlevels, such as but not limited to testosterone levels, is beneficial,such as but not limited to prostate cancer, catration-resistant prostatecancer, breast cancer, ovarian cancer, hair loss, benign prostatichyperplasia, acne vugaris, and androgenetic alopecia, among others.

In another aspect, the present invention is directed to the treatmentand prevention of chronic obstructive pulmonary diseases. Chronicobstructive pulmonary disease (COPD) is estimated to affect 32 millionpersons in the United States and is the fourth leading cause of death inthis country. Patients typically have symptoms of both chronicbronchitis and emphysema, but the classic triad also includes asthma.Most of the time COPD is secondary to tobacco abuse, although cysticfibrosis, alpha-1 antitrypsin deficiency, bronchiectasis, and some rareforms of bullous lung diseases may be causes as well. The invention isdirected to all such causes of COPD.

Patients with COPD are susceptible to many insults that can lead rapidlyto an acute deterioration superimposed on chronic disease. Quick andaccurate recognition of these patients along with aggressive and promptintervention may be the only action that prevents frank respiratoryfailure.

Pathophysiology:

COPD is a mixture of 3 separate disease processes that together form thecomplete clinical and pathophysiological picture. These processes arechronic bronchitis, emphysema and, to a lesser extent, asthma. Each caseof COPD is unique in the blend of processes; however, 2 main types ofthe disease are recognized.

Chronic Bronchitis.

In this type, chronic bronchitis plays the major role. Chronicbronchitis is defined by excessive mucus production with airwayobstruction and notable hyperplasia of mucus-producing glands. Damage tothe endothelium impairs the mucociliary response that clears bacteriaand mucus. Inflammation and secretions provide the obstructive componentof chronic bronchitis. In contrast to emphysema, chronic bronchitis isassociated with a relatively undamaged pulmonary capillary bed.Emphysema is present to a variable degree but usually is centrilobularrather than panlobular. The body responds by decreasing ventilation andincreasing cardiac output. This V/Q mismatch results in rapidcirculation in a poorly ventilated lung, leading to hypoxemia andpolycythemia.

Eventually, hypercapnia and respiratory acidosis develop, leading topulmonary artery vasoconstriction and cor pulmonale. With the ensuinghypoxemia, polycythemia, and increased CO₂ retention, these patientshave signs of right heart failure and are known as “blue bloaters.”

Emphysema.

The second major type is that in which emphysema is the primaryunderlying process. Emphysema is defined by destruction of airwaysdistal to the terminal bronchiole. Physiology of emphysema involvesgradual destruction of alveolar septae and of the pulmonary capillarybed, leading to decreased ability to oxygenate blood. The bodycompensates with lowered cardiac output and hyperventilation. This V/Qmismatch results in relatively limited blood flow through a fairly welloxygenated lung with normal blood gases and pressures in the lung, incontrast to the situation in blue bloaters. Because of low cardiacoutput, however, the rest of the body suffers from tissue hypoxia andpulmonary cachexia. Eventually, these patients develop muscle wastingand weight loss and are identified as “pink puffers.”

In the US, two thirds of men and one fourth of women have emphysema atdeath. Approximately 8 million people have chronic bronchitis and 2million have emphysema. COPD is the fourth leading cause of death in theUnited States, affecting 32 million adults. Men are more likely to haveCOPD than women, and COPD occurs predominantly in individuals older than40 years.

History:

Patients with COPD present with a combination of signs and symptoms ofchronic bronchitis, emphysema, and asthma. Symptoms include worseningdyspnea, progressive exercise intolerance, and alteration in mentalstatus. In addition, some important clinical and historical differencescan exist between the types of COPD. In the chronic bronchitis group,classic symptoms include the following: productive cough, withprogression over time to intermittent dyspnea; frequent and recurrentpulmonary infections; and progressive cardiac/respiratory failure overtime, with edema and weight gain. In the emphysema group, the history issomewhat different and may include the following set of classicsymptoms: a long history of progressive dyspnea with late onset ofnonproductive cough; occasional mucopurulent relapses; and eventualcachexia and respiratory failure.

Causes:

In general, the vast majority of COPD cases are the direct result oftobacco abuse. While other causes are known, such as alpha-1 antitrypsindeficiency, cystic fibrosis, air pollution, occupational exposure (e.g.,firefighters), and bronchiectasis, this is a disease process that issomewhat unique in its direct correlation to a human activity. Thepresent invention is directed to benefiting COPD regardless of the causeor pathogenic mechanisms.

Thus, the present invention is directed in one aspect to the treatmentand prevention of chronic obstructive pulmonary disease as describedabove. COPD includes, by way of non-limiting example, emphysema, chronicbronchitis and chronic asthma. Such conditions may arise from, amongother etiologies, cigarette smoking and other types of exposure totobacco smoke including second-hand smoke.

While the inventors have no duty to disclose the mechanism by whichcompounds embodied here operate and are not limited by that disclosure,the inventors herein have found that compounds that inhibit the activityof cytochrome P450, and in particular retinoic acid 4-hydroxylase, alsocalled CYP26, have been found to be beneficial for the purposesdescribed herein. Pharmaceutical compositions of such compounds, theirisomers and pharmaceutically acceptable salts, have been found to beuseful for such therapeutic purposes. Described herein are non-limitingexamples of inhibitors of cytochrome P450 useful for these purposes, butthe selections described are merely illustrative and not intending to belimiting to the use of CYP26 inhibition in general to benefit patientswith the aforementioned diseases.

Cytochrome P450 (CYP) is a family of enzymes is a very large and diversesuperfamily of hemoproteins found in all domains of life. They use aplethora of both exogenous and endogenous compounds as substrates inenzymatic reactions. Usually they form part of multicomponent electrontransfer chains, called P450-containing systems. Among the CYP family isCYP26 (also known as retinoic acid 4-hydroxylase) that metabolizesretinoic acid. Based on the studies described herein, it has been foundthat inhibiting the activity of the CYP26 in vivo is an effectivetherapeutic approach to the treatment and prevention of a number ofconditions and diseases as described herein. Any, means of inhibitingCYP26 is embodied herein for the therapeutic purposes herein. Moreover,any condition, injury or disease modulated by the in-vivo level of alltrans retenoic acid (ATRA) is encompassed herein. In certainembodiments, a compound of the invention can be administered to inhibitCYP26 to increase endogenous ATRA, and an exogenous retinoic acid can beadminstered to further enhance the benefit of any of the conditions anddiseases disclosed herein.

Furthermore, certain of the compounds embodied herein inhibit CYP17. Ina further embodiment, the compounds embodied herein inhibit both CYP26and CYP17, and may be referred to as dual inhibitors or dual CYP26 andCYP17 inhibitors. Furthermore, certain of the compounds embodied hereininhibit CYP19. In a further embodiment, the compounds embodied hereininhibit both CYP26 and CYP19, and may be referred to as dual inhibitorsor dual CYP26 and CYP19 inhibitors. Although disclosure of the mechanismby which embodiments herein operate is not required nor are Applicantsbound thereto, inhibitors of CYP26 as noted above increase the levels ofall-trans retinoic acid (ATRA), which increase is beneficial in variousconditions and diseases as described herein, such as but not limited tothe fibrotic process and dysproliferative diseases. Inhibitors of CYP17decrease levels of androgens such as testosterone, which decrease isbeneficial in various conditions and diseases as described herein, suchas but not limited to the dysproliferative and inflammatory diseases.

Furthermore, certain of the compounds embodied herein inhibit CYP 9. Ina further embodiment, the compounds embodied herein inhibit both CYP26and CYP19, and may be referred to as dual inhibitors or dual CYP26 andCYP19 inhibitors. In a further embodiment, the compounds embodied hereininhibit both CYP17 and CYP19, and may be referred to as dual inhibitorsor dual CYP17 and CYP19 inhibitors. Although disclosure of the mechanismby which embodiments herein operate is not required nor are Applicantsbound thereto, inhibitors of CYP26 as noted above increase the levels ofall-trans retinoic acid (ATRA), which increase is beneficial in variousconditions and diseases as described herein, such as but not limited tothe fibrotic process and dysproliferative diseases. Inhibitors of CYP17decrease levels of androgens such as testosterone, which decrease isbeneficial in various conditions and diseases as described herein, suchas but not limited to the dysproliferative and inflammatory diseases.Inhibitors of CYP19 decrease levels of estrogens, which decrease isbeneficial in various conditions and diseases as described herein, suchas but not limited to dysproliferative and inflammatory diseases.

Non-Limiting Examples of Clinical Uses of Compounds with Anti-FibroticActivity

1. Fibrotic Liver Disease:

Liver fibrosis is the scarring response of the liver to chronic liverinjury; when fibrosis progresses to cirrhosis, morbid complications candevelop. In fact, end-stage liver fibrosis or cirrhosis is the seventhleading cause of death in the United States, and afflicts hundreds ofmillions of people worldwide; deaths from end-stage liver disease in theUnited States are expected to triple over the next 10-15 years, mainlydue to the hepatitis C epidemic I. In addition to the hepatitis C virus,many other forms of chronic liver injury also lead to end-stage liverdisease and cirrhosis, including other viruses such as hepatitis B anddelta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis,extrahepatic obstructions (stones in the bile duct), cholangiopathies(primary biliary cirrhosis and sclerosing cholangitis), autoimmune liverdisease, and inherited metabolic disorders (Wilson's disease,hemochromatosis, and alpha-1 antitrypsin deficiency).

Treatment of liver fibrosis has focused to date on eliminating theprimary injury. For extrahepatic obstructions, biliary decompression isthe recommended mode of treatment whereas patients with Wilson's diseaseare treated with zinc acetate. In chronic hepatitis C infection,interferon has been used as antiviral therapies with limited response:˜20% when used alone or ˜50% response when used in combination withribavirin. In addition to the low-level of response, treatment withinterferon with or without ribavirin is associated with numerous severeside effects including neutropenia, thrombocytopenia, anemia,depression, generalized fatigue and flu-like symptoms, which aresufficiently significant to necessitate cessation of therapy. Treatmentsfor other chronic liver diseases such as hepatitis B, autoimmunehepatitis and Wilson's disease are also associated with many sideeffects, while primary binary cirrhosis, primary sclerosing cholangitisand non-alcoholic fatty liver disease have no effective treatment otherthan liver transplantation.

The advantage of treating fibrosis rather than only the underlyingetiology, is that antifibrotic therapies should be broadly applicableacross the full spectrum of chronic liver diseases. Whiletransplantation is currently the most effective cure for liver fibrosis,mounting evidence indicates that not only fibrosis, but even cirrhosisis reversible. Unfortunately patients often present with advanced stagesof fibrosis and cirrhosis, when many therapies such as antivirals can nolonger be safely used due to their side effect profile. Such patientswould benefit enormously from effective antifibrotic therapy, becauseattenuating or reversing fibrosis may prevent many late stagecomplications such as infection, asciites, and loss of liver functionand preclude the need for liver transplantation. The compounds of theinvention are beneficial for the treatment of the foregoing conditions,and generally are antifibrotic and/or antiapoptotic agents for this andother organ or tissues.

2. Hepatic Ischemia-Reperfusion Injury:

Currently, transplantation is the most effective therapeutic strategyfor liver fibrosis. However, in spite of the significant improvement inclinical outcome during the last decade, liver dysfunction or failure isstill a significant clinical problem after transplantation surgery.Ischemia-reperfusion (IR) injury to the liver is a majoralloantigen-independent component affecting transplantation outcome,causing up to 10% of early organ failure, and leading to the higherincidence of both acute and chronic rejection. Furthermore, given thedramatic organ shortage for transplantation, surgeons are forced toconsider cadaveric or steatotic grafts or other marginal livers, whichhave a higher susceptibility to reperfusion injury. In addition totransplantation surgery, liver IR injury is manifested in clinicalsituations such as tissue resections (Pringle maneuver), and hemorrhagicshock.

The damage to the postischemic liver represents a continuum of processesthat culminate in hepatocellular injury. Ischemia activates Kupffercells, which are the main sources of vascular reactive oxygen species(ROS) formation during the initial reperfusion period. In addition toKupffer cell-induced oxidant stress, with increasing length of theischemic episode, intracellular generation of ROS by xanthine oxidaseand in particular mitochondria may also contribute to liver dysfunctionand cell injury during reperfusion. Endogenous antioxidant compounds,such as superoxide dismutase, catalase, glutathione, alphatocopherol,and beta-carotene, may all limit the effects of oxidant injury but thesesystems can quickly become overwhelmed by large quantities of ROS. Workby Lemasters and colleagues, has indicated that in addition to formationof ROS, intracellular calcium dyshomeostasis is a key contributor toliver IR injury. Cell death of hepatocytes and endothelial cells in thissetting is characterized by swelling of cells and their organelles,release of cell contents, eosinophilia, karyolysis, and induction ofinflammation, characteristic of oncotic necrosis. More recent reportsindicate that liver cells also die by apoptosis, which ismorphologically characterized by cell shrinkage, formation of apoptoticbodies with intact cell organelles and absence of an inflammatoryresponse.

Indeed, minimizing the adverse effects of IR injury could significantlyincrease the number of patients that may successfully undergo livertransplantation. Pharmacologic interventions that reduce cell deathand/or enhance organ regeneration represent a therapeutic approach toimprove clinical outcome in liver transplantation, liver surgery withvascular exclusion and trauma and can therefore reduce recipient/patientmorbidity and mortality. The compounds of the invention are beneficialfor the treatment of the foregoing conditions.

3. Cerebral Infarction.

Stroke and cerebrovascular disease are a leading cause of morbidity andmortality in the US: at least 600,000 Americans develop strokes eachyear, and about 160,000 of these are fatal. Research on thepathophysiological basis of stroke has produced new paradigms forprevention and treatment, but translation of these approaches intoimproved clinical outcomes has proved to be painfully slow. Preventivestrategies focus primarily on reducing or controlling risk factors suchas diabetes, hypertension, cardiovascular disease, and lifestyle; inpatients with severe stenosis, carotid endarterectomy may be indicated.Cerebral angioplasty is used investigationally, but the high restenosisrates observed following coronary angioplasty suggest this approach maypose unacceptable risk for many patients. Therapeutic strategies focusprimarily on acute treatment to reduce injury, in the ischemic penumbra,the region of reversibly damaged tissue surrounding an infarct.Thrombolytic therapy has been shown to improve perfusion to the ischemicpenumbra, but it must be administered within three hours of the onset ofinfarction. Several neuroprotective agents that block specific tissueresponses to ischemia are promising, but none have yet been approved forclinical use. While these therapeutic approaches limit damage in theischemic penumbra, they do not address the underlying problem ofinadequate blood supply due to occluded arteries. An alternativestrategy is to induce formation of collateral blood vessels in theischemic region; this occurs naturally in chronic ischemic conditions,but stimulation of vascularization via therapeutic angiogenesis haspotential therapeutic benefit.

Recent advances in aging have confirmed the pathophysiological basis ofthe clinical observations of evolving stroke. Analysis of impairedcerebral blood flow (CBF) in the region of an arterial occlusionsupports the hypothesis that a central region of very low CBF, theischemic core, is irreversibly damaged, but damage in surrounding orintermixed zones where CBF is of less severely reduced, the ischemicpenumbra, can be limited by timely reperfusion. Plate recently reviewedthe evidence suggesting that therapeutic angiogenesis may be useful fortreatment or prevention of stroke. First, analysis of cerebralvasculature in stroke patients showed a strong correlation between bloodvessel density and survival and a higher density of microvessels in theischemic hemisphere compared to the contralateral region. Second,studies in experimental models of cerebral ischemia indicate expressionof angiogenic growth factors such as vascular endothelial growth factor(VEGF) or HGF/SF is induced rapidly in ischemic brain tissue. Third,administration of VEGF or HGF/SF can reduce neuronal damage and infarctvolume in animal models. Similar evidence provided the rationale fordeveloping therapeutic angiogenesis for treating peripheral andmyocardial ischemia, which has been shown to produce clinicalimprovements in early studies in humans. The compounds of the invention,having similar antifibrotic properties, are beneficial for the treatmentof the foregoing conditions.

4. Ischemic heart disease is a leading cause of morbidity and mortalityin the US, afflicting millions of Americans each year at a cost expectedto exceed 5300 billion/year. Numerous pharmacological and interventionalapproaches are being developed to improve treatment of ischemic heartdisease including reduction of modifiable risk factors, improvedrevascularization procedures, and therapies to halt progression and/orinduce regression of atherosclerosis. One of the most exciting areas ofresearch for the treatment of myocardial ischemia is therapeuticangiogenesis. Recent studies support the concept that administration ofangiogenic growth factors, either by gene transfer or as a recombinantprotein, augments nutrient perfusion through neovascularization. Thenewly developed, supplemental collateral blood vessels constituteendogenous bypass conduits around occluded native arteries, improvingperfusion to ischemic tissue. The compounds of the invention arebeneficial for the treatment of the foregoing conditions.

5. Renal Disease.

Chronic renal dysfunction is a progressive, degenerative disorder thatultimately results in acute renal failure and requires dialysis as anintervention, and renal transplantation as the only potential cure.Initiating conditions of renal dysfunction include ischemia, diabetes,underlying cardiovascular disease, or renal toxicity associated withcertain chemotherapeutics, antibiotics, and radiocontrast agents. Mostend-stage pathological changes include extensive fibrinogenesis,epithelial atrophy, and inflammatory cell infiltration into the kidneys.

Acute renal failure is often a complication of diseases includingdiabetes or renal ischemia, procedures such as heminephrectomy, or as aside effect of therapeutics administered to treat disease. The widelyprescribed anti-tumor drug cis-diamminedichloroplatinum (cisplatin), forexample, has side effects that include a high incidence ofnephrotoxicity and renal dysfunction, mainly in the form of renaltubular damage that leads to impaired glomerular filtration.Administration of gentamicin, aminoglycoside antibiotic, or cyclosporinA, a potent immunosuppressive compound, causes similar nephrotoxicity.The serious side effects of these effective drugs restrict their use.The development of agents that protect renal function and enhance renalregeneration after administration of nephrotoxic drugs will be ofsubstantial benefit to numerous patients, especially those withmalignant tumors, and may allow the maximal therapeutic potentials ofthese drugs to be realized. The compounds of the invention arebeneficial for the treatment of the renal diseases mentioned above,

6. Lung (Pulmonary) Fibrosis.

Idiopathic pulmonary fibrosis (IPF) accounts for a majority of chronicinterstitial lung diseases, and has an estimated incidence rate of 10.7cases for 100,000 per year, with an estimated mortality of 50-70%. IPFis characterized by an abnormal deposition of collagen in the lung withan unknown etiology. Although the precise sequence of the pathogenicsequelae is unknown, disease progression involves epithelial injury andactivation, formation of distinctive subepithelialfibroblast/myofibroblast foci, and excessive extracellular matrixaccumulation. The development of this pathological process is precededby an inflammatory response, often dominated by macrophages andlymphocytes, which is mediated by the local release of chemoattractantfactors and upregulation of cell-surface adhesion molecules. Lung injuryleads to vasodilatation and leakage of plasma proteins into interstitialand alveolar spaces, as well as activation of the coagulation cascadeand deposition of fibrin. Fibroblasts migrate into this provisionalfibrin matrix where they synthesize extracellular matrix molecules. Innon-pathogenic conditions, excess fibrin is usually degraded by plasmin,a proteinase that also has a role in the activation of matrixmetalloproteinases (MMPs). Activated MMPs degrade extracellular matrixand participate in fibrin removal, resulting in the clearance of thealveolar spaces and the ultimate restoration of red tissues. Inpathological conditions, however, these processes can lead toprogressive and irreversible changes in lung architecture, resulting inprogressive respiratory insufficiency and an almost universally terminaloutcome in a relatively short period of time. Fibrosis is the finalcommon pathway of a variety of lung disorders, and in this context, thediagnosis of pulmonary fibrosis implies the recognition of an advancedstage in the evolution of a complex process of abnormal repair. Whilemany studies have focused on inflammatory mechanisms for initiating thefibrotic response, the synthesis and degradation the extracellularmatrix represent the central event of the disease. It is this processthat presents a very attractive site of therapeutic intervention.

The course of IPF is characterized by progressive respiratoryinsufficiency, leading to death within 3 to 8 years from the onset ofsymptoms. Management of interstitial lung disease in general, and inparticular idiopathic pulmonary fibrosis, is difficult, unpredictableand unsatisfactory. Attempts have been made to use antiinflammatorytherapy to reverse inflammation, relief, stop disease progression andprolong survival. Corticosteroids are the most frequently usedantiinflammatory agents and have been the mainstay of therapy for IPFfor more than four decades, but the efficacy of this approach isunproven, and toxicities are substantial. No studies have compareddiffering dosages or duration of corticosteroid treatment in matchedpatients. Interpretation of therapy efficacy is obscured by severalfactors including heterogeneous patient populations, inclusion ofpatients with histologic entities other than usual interstitialpneumonia, lack of objective, validated endpoints, and differentcriteria for “response.” Cytotoxic drugs such as Azathioprine andcyclophosobamide have also being used in combination with low dose oralcorticosteroids. The results of such treatments vary from no improvementto significant prolongation of survival. Overall, currently availabletreatments for lung fibrosis are sub-optimal. Potential new therapieshave emerged from the use of animal models of pulmonary fibrosis andrecent advances in the cellular and molecular biology of inflammatoryreactions. Such therapies involve the use of cytokines, oxidants andgrowth factors that are elaborated during the fibrotic reaction. Despitethe use of newer strategies for treatment, the overall prognosis forpatients with interstitial lung disease has had little quantifiablechange, and the population survival remains unchanged for the last 30years. Interferon gamma (IFN) may be effective in the treatment of IPFin some patients but its role is controversial. Literature indicatedthat IFN-gamma may be involved in small airway disease in silicoticlung. Others showed that IFN gamma mediates, bleomycin-induced pulmonaryinflammation and fibrosis. The compounds of the invention are beneficialfor the treatment of the foregoing condition, among other fibroticdiseases.

7. Demyelinating Diseases.

Demyelinating diseases are those in which myelin is the primary target.They fall into two main groups: acquired diseases (i.e., multiplesclerosis) and hereditary neurodegenerative disorders (i.e., theleukodystrophies). Although their causes and etiologies are different,they have the same outcome: central nervous system (CNS) demyelination.Without myelin, nerve impulses are slowed or stopped, leading to aconstellation of neurological symptoms. Multiple sclerosis (MS) is themost common demyelinating disease, which usually manifests itselfbetween the 20th and 50th years of life. Current estimates are thatapproximately 2.5 million people worldwide have MS, with between 250,000and 350,000 cases in the United States, 50,000 cases in Canada, 130,000cases in Germany, 85,000 cases in the United Kingdom, 75,000 cases inFrance, 50,000 cases in Italy, and 11,000 cases in Switzerland,

MS attacks the white matter of the CNS. In its classic manifestation(90% of all cases), it is characterized by alternatingrelapsing/remitting phases with the periods of remission growing shorterover time. Its symptoms include any combination of spastic paraparesis,unsteady gait, diplopia, and incontinence.

Other demyelinating diseases include leukodystrophies: metachromaticleukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe'sdisease, phenylketonuria, Canavan disease, Pelizaeus-Merzbacher diseaseand Alexander's disease. The first six are storage disorders. The lackor the malfunctioning of an enzyme causes a toxic buildup of chemicalsubstances. In Pelizaeus-Merzbacher disease myelin is never formed(dysmyelination) because of a mutation in the gene that produces a basicprotein of CNS myelin. The etiology of Alexander's disease remainslargely unknown.

8. Male Hormone Related Diseases.

Diseases such as prostate cancer, castration resistant prostate cancer,benign prostatic hypertrophy and male hair loss are amenable to therapyand even prevention using compounds embodied herein. Furthermore, otherbenefit of compounds include use in male contraception; treatment of avariety of male hormone-related conditions such as hypersexuality andsexual deviation; treatment of conditions including benign prostatichyperplasia, acne vugaris, and androgenetic alopecia, purposefullypreventing or counteracting masculinisation in the case of transsexualwomen undergoing sex reassignment therapy; an antineoplastic agent andpalliative, adjuvant or neoadjuvant hormonal therapy in prostate cancer;and decreasing the incidence of halting or causing a regression ofprostate cancer.

Prostate cancer is one of the most common cancers in men around theworld, and is one of the leading causes of cancer death in men in theUnited States. Current standard treatment for local prostate cancer issurgery and radiation. Unfortunately, the cancer relapses in one-thirdof the treated patients. Together with patients diagnosed with advancedprostate cancer, they are treated with surgical castration or chemicalcastration, which is called hormone therapy (HT). Often HT is alsocombined with drugs acting as androgen receptor antagonists. Hormonetherapy is highly effective for controlling cancer cells in most ofpatients with advanced prostate cancer. However, the prostate cancercells eventually adapt to the low androgen environment and becomeresistant to HT. As a result, the cancer will recur in almost all suchpatients in 2-5 years. Androgen receptor antagonist drugs, such asflutamide and bicalutamide, were originally designed to avoid the sideeffects of HT and to overcome resistance in prostate cancer patients.Although these androgen receptor antagonists work well as a co-treatmentwith IT in naive advanced prostate cancer patients, their efficacyagainst refractory prostate cancer, as a single agent, or co-treatment,has been limited. There have been reports that androgen agonism wasobserved for hydroxyfluamide (the active form of flutamide) andbicalutamide. The residual agonistic effect may be responsible for thedrugs' ineffectiveness in overcoming resistance. The therapeutic benefitof these androgen receptor antagonist drugs have also been hampered bysignificant side effects such as liver toxicities associated withflutamide and bicalutamide.

In another embodiment, compounds embodied here are useful for thetreatment of prostate cancer. Prostate cancer affects 1 in 6 men. Withthe exception of skin cancer, prostate cancer is the most common cancerin men. It is the second most common cause of cancer-related death. In2007, 223,307 men were diagnosed with prostate cancer in the UnitedStates and 29,093 men died from the disease.

Castration Resistant Prostate Cancer. Depletion of gonadal testosteronethrough androgen deprivation therapy (ADT) is the frontline treatmentfor advanced prostate cancer and may be accomplished by medical orsurgical castration. Other hormonal interventions for prostate cancerinclude further depletion of androgens by inhibition of adrenal androgensynthesis, direct inhibition of the androgen receptor (AR), andinhibition of 5α-reductase, the enzyme that converts testosterone to themore potent dihydrotestosterone (DHT). Although the majority of prostatetumors initially respond to ADT, eventually the metastatic diseasealmost invariably progresses to castration-resistant prostate cancer(CRPC). Treatments for use in CRPC patients include mitoxantrone,radioactive isotopes, zoledronic acid and docetaxel. Of these, docetaxelis the only approved systemic agent that has been shown to improveoverall survival, albeit just by a couple of months. There continues tobe a great unmet need for more effective treatments in CRPC.

In another embodiment, compounds embodied here are useful for thetreatment of breast and ovarian cancer. In 2008, breast cancer caused458,503 deaths worldwide (13.7% of cancer deaths in women). Breastcancer is more than 100 times more common in women than breast cancer inmen, although males tend to have poorer outcomes due to delays indiagnosis. In 2004, in the United States, 25,580 new cases of ovariancancer were diagnosed and 16,090 women died of ovarian cancer. The riskincreases with age and decreases with pregnancy. Lifetime risk is about1.6%, but women with affected first-degree relatives have a 5% risk.Women with a mutated BRCA1 or BRCA2 gene carry a risk between 25% and60% depending on the specific mutation.

Dysproliferative diseases. Dysproliferative disorders refers in oneembodiment to abnormal proliferation of cells, includinghyperproliferative disorders, hyperplasia, metaplasia, dysplasia, by wayof non-limiting examples, as described below.

Hyperproliferative Disorders. In certain embodiments, compounds andcompositions of the invention can be used to treat hyperproliferativedisorders, including neoplasms. Examples of hyperproliferative disordersthat can be treated by compounds and compositions of the inventioninclude, but are not limited to neoplasms located in the: colon,abdomen, bone, breast, digestive system, liver, pancreas, peritoneum,endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary,thymus, thyroid), eye, head and neck, nervous (central and peripheral),lymphatic system, pelvis, skin, soft tissue, spleen, thorax, andurogenital tract.

Similarly, other hyperproliferative disorders can also be treated bycompounds and compositions of the invention. Examples of suchhyperproliferative disorders include, but are not limited to: acutechildhood lymphoblastic leukemia, acute lymphoblastic leukemia, acutelymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma,adult (primary) hepatocellular cancer, adult (primary) liver cancer,adult acute lymphocytic leukemia, adult acute myeloid leukemia, adultHodgkin's disease, adult Hodgkin's lymphoma, adult lymphocytic leukemia,adult non-Hodgkin's lymphoma, adult primary liver cancer, adult softtissue sarcoma, AIDS-related lymphoma, AIDS-related malignancies, analcancer, astrocytoma, bile duct cancer, bladder cancer, bone cancer,brain stem glioma, brain tumors, breast cancer, cancer of the renalpelvis and ureter, central nervous system (primary) lymphoma, centralnervous system lymphoma, cerebellar astrocytoma, cerebral astrocytoma,cervical cancer, childhood (primary) hepatocellular cancer, childhood(primary) liver cancer, childhood acute lymphoblastic leukemia,childhood acute myeloid leukemia, childhood brain stem glioma, childhoodcerebellar astrocytoma, childhood cerebral astrocytoma childhoodextracranial germ cell tumors, childhood Hodgkin's disease, childhoodHodgkin's lymphoma, childhood hypothalamic and visual pathway glioma,childhood lymphoblastic leukemia, childhood medulloblastoma, childhoodnon-Hodgkin's lymphoma, childhood pineal and supratentorial primitiveneuroectodermal tumors, childhood primary liver cancer, childhoodrhabdomyosarcoma, childhood soft tissue sarcoma, childhood visualpathway and hypothalamic glioma, chronic lymphocytic leukemia, chronicmyelogenous leukemia, colon cancer, cutaneous T-cell lymphoma, endocrinepancreas islet cell carcinoma, endometrial cancer, ependymoma,epithelial cancer, esophageal cancer, Ewing's sarcoma and relatedtumors, exocrine pancreatic cancer, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer,female breast cancer, Gaucher's disease, gallbladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal tumors, germcell tumors, gestational trophoblastic tumor, hairy cell leukemia, headand neck cancer, hepatocellular cancer, Hodgkin's disease, Hodgkin'slymphoma, hypergammaglobulinemia, hypopharyngeal cancer, intestinalcancers, intraocular melanoma, islet cell carcinoma, islet cellpancreatic cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer,lip and oral cavity cancer, liver cancer, lung cancer,lymphoproliferative disorders, macroglobulinemia, male breast cancer,malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma,mesothelioma, metastatic occult primary squamous neck cancer, metastaticprimary squamous neck cancer, metastatic squamous neck cancer, multiplemyeloma, multiple myeloma/plasma cell neoplasm, myelodysplasticsyndrome, myelogenous leukemia, myeloid leukemia, myeloproliferativedisorders, nasal cavity and paranasal sinus cancer, nasopharyngealcancer, neuroblastoma, non-Hodgkin's lymphoma during pregnancy,nonmelanoma skin cancer, non-small cell lung cancer, occult primarymetastatic squamous neck cancer, oropharyngeal cancer, osteo-/malignantfibrous sarcoma, osteosarcoma/malignant fibrous histiocytoma,osteosarcoma/malignant fibrous histiocytoma of bone, ovarian epithelialcancer, ovarian germ cell tumor, ovarian low malignant potential tumor,pancreatic cancer, paraproteinemias, purpura, parathyroid cancer, penilecancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm/multiplemyeloma, primary central nervous system lymphoma, primary liver cancer,prostate cancer, rectal cancer, renal cell cancer, renal pelvis andureter cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer,sarcoidosis sarcomas, Sezary syndrome, skin cancer, small cell lungcancer, small intestine cancer, soft tissue sarcoma, squamous neckcancer, stomach cancer, supratentorial primitive neuroectodermal andpineal tumors, T-cell lymphoma, testicular cancer, thymoma, thyroidcancer, transitional cell cancer of the renal pelvis and ureter,transitional renal pelvis and ureter cancer, trophoblastic tumors,ureter and renal pelvis cell cancer, urethral cancer, uterine cancer,uterine Sarcoma, vaginal Cancer, visual pathway and hypothalamic glioma,vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, and anyother hyperproliferative disease, located in an organ system listedabove.

In another embodiment, the compounds and compositions of the inventionare used to prevent, and/or treat premalignant conditions and to preventprogression to a neoplastic or malignant state, including but notlimited to those disorders described above. Such uses are indicated inconditions known to precede or suspected of preceding progression toneoplasia or cancer, in particular, where non-neoplastic cell growthconsisting of hyperplasia, metaplasia, or most particularly, dysplasiahas occurred (for review of such abnormal growth conditions, see Robbinsand Angell, 1976, Basic Pathology, 2d Ed., W. B. Saunders Co.,Philadelphia, pp. 68-79)

Hyperplasia is a form of controlled cell proliferation, involving anincrease in cell number in a tissue or organ, out significant alterationin structure or function. Hyperplastic disorders which can be prevented,and/or treated with compounds and compositions of the invention include,but are not limited to, angiofollicular mediastinal lymph nodehyperplasia, angiolymphoid hyperplasia with eosinophilia, atypicalmelanocytic hyperplasia, basal cell hyperplasia, benign giant lymph nodehyperplasia, cementum hyperplasia, congenital adrenal hyperplasia,congenital sebaceous hyperplasia, cystic hyperplasia, cystic hyperplasiaof the breast, denture hyperplasia, ductal hyperplasia, endometrialhyperplasia, fibromuscular hyperplasia, focal epithelial hyperplasia,gingival hyperplasia, inflammatory fibrous hyperplasia, inflammatorypapillary hyperplasia, intravascular papillary endothelial hyperplasia,nodular hyperplasia of prostate, nodular regenerative hyperplasia,pseudoepitheliomatous hyperplasia, senile sebaceous hyperplasia, andverrucous hyperplasia.

Metaplasia is a form of controlled cell growth in which one type ofadult or fully differentiated cell substitutes for another type of adultcell. Metaplastic disorders which can be prevented, and/or treated withcompounds and compositions of the invention include, but are not limitedto, agnogenic myeloid metaplasia, apocrine metaplasia, atypicalmetaplasia, autoparenehymatous metaplasia, connective tissue metaplasia,epithelial metaplasia, intestinal metaplasia, metaplastic anemia,metaplastic ossification, metaplastic polyps, myeloid metaplasia,primary myeloid metaplasia, secondary myeloid metaplasia, squamousmetaplasia, squamous metaplasia of amnion, and symptomatic myeloidmetaplasia.

Dysplasia is frequently a forerunner of cancer, and is found mainly inthe epithelia; it is the most disorderly form of non-neoplastic cellgrowth, involving a loss in individual cell uniformity and in thearchitectural orientation of cells. Dysplastic cells often haveabnormally large, deeply stained nuclei, and exhibit pleomorphism.Dysplasia characteristically occurs where there exists chronicirritation or inflammation. Dysplastic disorders which can be prevented,and/or treated with compounds and compositions of the invention include,but are not limited to, anhidrotic ectodermal dysplasia, anterofacialdysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia;bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia,chondroectodermal dysplasia, cleidocranial dysplasia, congenitalectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsaldysplasia, craniometaphysical dysplasia, dentin dysplasia, diaphysicaldysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmicdysplasia; dysplasia epiphysialis hemimelia, dysplasia epiphysialismultiplex, dysplasia epiphysialis punctata, epithelial dysplasia,faciodnzitogenital dysplasia, familial fibrous dysplasia of jaws,familial white folded dysplasia, fibromuscular dysplasia, fibrousdysplasia of bone, florid osseous dysplasia, hereditary renal-retinaldysplasia; hidrotic ectodermal dysplasia, hypohidrotic ectodermaldysplasia, lymphopenic thymic dysplasia, mammary dysplasia,mandibulofacial dysplasia, metaphysical dysplasia, Mondini dysplasia,monostotic fibrous dysplasia, mucoepithelial dysplasia, multipleepiphysial dysplasia, oculoauriculovertebral dysplasia,oculodentodigital dysplasia, oculovertebral dysplasia, odontogenicdysplasia, opthalmomandibulomelic dysplasia, periapical cementaldysplasia, polyostotic fibrous dysplasia, pseudoachondroplasticspondyloepiphysial dysplasia, retinal dysplasia, septo-optic dysplasia,spondyloepiphysial dysplasia, and ventriculoradial dysplasia.

Additional pre-neoplastic disorders which can be prevented, and/ortreated with compounds and compositions of the invention include, butare not limited to, benign dysproliferative disorders (e.g., benigntumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps,colon polyps, and esophageal dysplasia), leukoplakia, keratoses, Bowen'sdisease, Farmer's Skin, solar cheilitis, and solar keratosis.

In certain embodiments, the present invention relates to theaforementioned method, wherein said cancer or other dysproliferativedisease is selected from the group consisting of leukemias, myeloidleukemias, lymphocytic leukemias, lymphomas, myeloproliferativediseases, solid tumors, sarcomas, carcinomas, fibrosarcoma, myxosarcoma,liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, andretinoblastoma.

In certain embodiments, the present invention relates to theaforementioned method, wherein said cancer or other dysproliferativedisease is selected from the group consisting of brain tumors, glioma,diabetic retinopathy, and pancreatic cancers.

In certain embodiments, the present invention relates to theaforementioned method, wherein said cancer or other dysproliferativedisease is selected from the group consisting of arteriovenous (AV)malformations, psoriasis, benign prostatic hypertrophy, cutaneous fungalinfections, warts, birthmarks, moles, nevi, skin tags, lipomas, angiomashemangiomas, and cutaneous lesions.

9. Inflammatory Disorders.

Another aspect of the invention related to a method for treating aninflammatory disease or disorder such as rheumatoid arthritis, in which,for example, inappropriate angiogenesis leads to the formation of pannusand associated pathology in a joint, or neovascularization from theretina in diabetic patients leading to blindness.

Rheumatoid arthritis (RA) is a chronic disease, Characterized mainly byinflammation of the lining, or synovium, of the joints. It can lead tolong-term joint damage, resulting in chronic pain, loss of function anddisability. The disease progresses in three stages. The first stage isthe swelling of the synovial lining, causing pain, warmth, stiffness,redness and swelling around the joint. Second is the rapid division andgrowth of cells, or pannus, which causes the synovium to thicken. In thethird stage, the inflamed cells release enzymes that may digest bone andcartilage, often causing the involved joint to lose its shape andalignment, additional pain, and loss of movement. Because it is achronic disease, RA continues indefinitely and may never resolve.Frequent flares in disease activity can occur. RA is also a systemicdisease, with the potential to affect other organs in the body,

Approximately 2.1 million people in the United States, or 1% of thepopulation, have RA. It can affect anyone, including children, but 70%of individuals with RA are women. Onset usually occurs between 30 and 50years of age. RA often goes into remission in pregnant women, althoughsymptoms tend to increase in intensity after delivery. RA develops moreoften than expected the year after giving birth. While women are two tothree times more likely to get RA than men, men tend to be more severelyaffected when afflicted,

Exemplary Assays

Efficacy of the compounds of the invention on the aforementioneddisorders and diseases or the potential to be of benefit for theprophylaxis or treatment thereof may be demonstrated in various studies,ranging from biochemical effects evaluated in vitro and effects on cellsin culture, to in-vivo models of disease, wherein direct clinicalmanifestations of the disease can be observed and measured, or whereinearly structural and/or functional events occur that are established tobe involved in the initiation or progression of the disease. Thepositive effects of the compounds of the invention have beendemonstrated in certain assays and can be assayed in a variety of suchassays and models, for a number of diseases and disorders. One skilledin the art can readily determine following the guidance described hereinwhether a compound of the invention is an inhibitor of CYP26 or CYP17(or both), or an inhibitor of CYP19, or an inhibitor of CYP26 and CYP19,or an inhibitor of CYP17 and CYP19, and is useful therapeutically.

1. Hepatic Disease

-   -   a. Antifibrotic Activity in Hepatic Stellate Cells. Serum        starved (activated) LX2 cells (an immortalized human hepatic        stellate cell line) that are treated with a compound of the        invention will show a decrease in collagen I mRNA expression, as        well as expression of other fibrotic marker genes, related to        significant antifibrotic activity.    -   b. Liver Disease endpoints. The rodent model of thioacetamide        (TAA)-induced liver fibrosis and the rat bile duct ligation        model of fibrosis shows improvements by the compounds of the        invention, in a panel of functional and histological tests:        gross morphology, mass, portal pressure, presence of ascites,        enzymes (AST, ALT), collagen content, interstitial fibrosis and        alpha-smooth muscle actin and MMP-2.

2. Protection Against Renal Dysfunction

-   -   a. Clinical model: arterial occlusion. In a mouse model of        transient unilateral renal artery occlusion, male ICR mice are        anesthetized and the left renal artery occluded with a        microvascular clamp. After 30 minutes, the clamp is removed and        the kidney allowed to reperfuse. Ten minutes into reperfusion        the nonischemic contralateral kidney is excised. Animals are        treated daily with vehicle or compound of the invention until        the day of sacrifice. Serum creatinine, BUN and urine protein        levels, measured at 1, 4 and 7 days post ischemia are used to        determine the ability of compounds of the invention to restore        function to injured kidneys. In order to create a more severe        renal injury, animals are subjected to 45 minutes of ischemia.    -   b. Protection against HgCl₂-induced renal injury. In a study        mice are injected with a high dose of HgCl₂ (7 mg/kg, s.c.) and        divided into treatment groups. Animals in the first group        receive vehicle or a compound of the invention on the day of        toxin injection and daily thereafter for 3 days, and are        euthanized inn day 4. Blood samples that are collected prior to        HgCl₂ injection, on day 2 and on day 4 are analyzed for serum        creatinine. In the second group, treatment with vehicle or        compound begins on the day following toxin injection (i.e., 24 h        delayed treatment) and daily thereafter until day 6. Mice are        euthanized on day 7. Blood samples collected prior to HgCl₂        injection; on day 4 and day 7 are analyzed for serum creatinine        and BUN, Serum creatinine, BUN, and development of tubular        necrosis are measured to indicate positive clinical activity,    -   c. Protection against ureteral obstruction. The effects of the        compounds of invention on renal injury secondary to ureteral        obstruction are examined in a mouse model of transient        unilateral renal artery occlusion. Kidneys from mice subject to        unilateral ureteral obstruction for 2 weeks are examined for        histological evidence of injury and protection by compound        treatment, Immunohistochemical staining is performed for        fibronectin, proliferating cell nuclear antigen, and TUNEL (for        an assessment of apoptosis). Trichrome staining is also        performed to assess the extent of collagen formation as an        indication of interstitial fibrosis.

3. Cerebral Infarction/Stroke

-   -   a. Neuroprotective Effects in Brain Tissue. Cerebral infarction        is induced in rats by middle cerebral artery occlusion (MCAO)        for 24 hr. Test compound or vehicle is administered at −24, 0,        and 8 hr. Sections of the brain are then examined for cell death        by staining with a tetrazolium compound        (2,3,5-Triphenyl-2H-tetrazolium chloride, or TTC). Normal rat        brains exhibit a red staining due to TTC reduction whereas areas        containing dead cells are white.

4. Myocardial Infarction

-   -   a. Ability of the compounds of the invention to inhibit        apoptosis in a rat model of myocardial infarction (as mentioned        above). Hearts from rats subject to left coronary artery        ligation are treated with compound (or vehicle control) by        direct injection and 24 hours later sectioned and TUNEL stained.        Treatment is associated with a significant reduction in the        number of apoptotic nuclei.    -   b. Clinical model. In a rat ischemia model, myocardial        infarction is induced by anterior descending artery occlusion.        The infarction is evident by an increase in positive TUNEL        staining, indicating DNA fragmentation in late-stage apoptosis.        Treatment with compounds of the invention greatly reduces the        extent of TUNEL staining.

5. Transplantation and Organ Preservation

-   -   a. The viability of organs and tissues harvested and transported        for transplant is currently optimally maintained by bathing and        transport in storage solutions such as the University of        Wisconsin (UW) cold storage solution (100 mM KH₂PO₄, 5 mM MgSO₄        100 mM potassium lactobionate, 1 mM allopurinol, 3 mM        glutathione, 5 mM adenosine, 30 mM raffinose, 50 g/liter of        hydroxyethyl starch, 40 units/liter of insulin, 16 mg/liter of        dexamethasone, 200,000 units/liter of penicillin, pH 7.4;        320-330 mOsM) (Ploeg R J, Goossens D, Vreugdenhil P. McAnulty J        F, Southard J H, Belzer F O. Successful 72-hour cold storage        kidney preservation with UW solution. Transplant Proc. 1988        February; 20(1 Suppl 1):935-8.). To further enhance the        viability of transplanted organs and tissues, inhibit apoptosis        and promote vascularization thereof, one or more compounds of        the invention may in included in this or any other storage        solution, as well as perfused into the donor or donor organ        prior to harvesting, and administered to the recipient        systemically and/or locally into the transplanted organ or        transplant site.

6. Lung Fibrosis

-   -   a. In order to assess the effects of test compounds on pulmonary        fibrosis a well-established mouse model of bleomycin-induced        lung injury is used. Male C57BL/6 mice (20-30 g, n=10/group) are        treated with bleomycin (0.06 U/20 gram body weight) or saline        via intratracheal administration. Bleomycin-treated mice are        divided into 2 groups. Compounds of the invention or vehicle is        administered daily until sacrifice on day 12. Right lung samples        from the mice are then harvested for analysis. Tissues are        sectioned and stained with modified Masson's Trichrome and are        analyzed for interstitial fibrosis. The Ashcroft scale is used        to obtain a numerical fibrotic score with each specimen being        scored independently by two histopathologists, and the mean of        their individual scores considered as the fibrotic score.

7. Emphysema

-   -   a. The porcine pancreatic elastase (PPE)-induced emphysema        murine model can be used. For the induction of emphysema, the        protocol described in the literature by Takahashi and colleagues        (Takahashi S, Nakamura H, Seki M et al. Reversal of        elastase-induced pulmonary emphysema and promotion of alveolar        epithelial cell proliferation by simvastatin in mice. Am J        Physiol Lung Cell Mol Physiol 2008 May; 294(5):L882-L890) is        followed. Porcine pancreatic elastase (PPE) is obtained from        Sigma (St. Louis, Mo.; Catalog #E7885) and mice are 8-wk-old        male C57BL/6 mice (Charles River Laboratories). Animals are        anesthetized and receive 20 μg of PPE in 50 μl of saline by        surgical intra-tracheal instillation or 50 μl of saline alone        (sham control group) on day 0. The day after PPE-instillation,        the mice are randomly divided into two groups and receive daily        administration by oral gavage of either test compound in water        (final concentration 10 mg/kg qd, group designated “TC”), or        water (vehicle control group) in a volume of 100 μL. The        administration of compound or vehicle is continued for 3½ weeks.        At the end of the experiment, animals are weighed and animals        are sacrificed before determining arterial blood gas and        isolation of lungs for histo-morphology and histo-immunology.        Treatment measures include 1) effects on arterial oxygen levels.        Arterial oxygen levels are an indicator of pulmonary function,        and several studies have indicated reduced arterial oxygen in        patients suffering from COPD and other pulmonary disorders        (Celli B R, Cote C G, Lareau S C, Meek P M. Predictors of        Survival in COPD: more than just the FEV1. Respir Med 2008 June;        102 Suppl 1:S27-S35). To evaluate the arterial oxygen pressure,        blood samples are withdrawn from the abdominal artery and blood        gas measurements were performed using a Siemens Rapidlab 248        blood gas analyzer. The arterial oxygen pressure in the test        compound treated PPE-exposed animals is significantly higher        than the pO2 of vehicle treated animals. 2) To evaluate the        effects of test compound on lung architecture,        histomorphological analyses are carried out in H&E stained        histological sections from paraffin embedded fixed lungs. The        mean alveolar diameter is calculated by determining the mean        linear intercept (Lm) from the analysis of 5 random fields in        6-10 lung slides in the different treatment groups. Typically,        treatment with elastase results in an increase in alveolar        diameter from an average of 42.5±1.6 μm in the sham operated        animals to 56.5±5.8 μm in the elastase treated vehicle animals        (Takahashi S, Nakamura H, Seki M et al. Reversal of        elastase-induced pulmonary emphysema and promotion of alveolar        epithelial cell proliferation by simvastatin in mice. Am J        Physiol Lung Cell Mol Physiol 2008 May; 294(5):L882-L890;        Plantier L. Marchand-Adam S, Alnico V G et al. Keratinocyte        growth factor protects against elastase-induced pulmonary        emphysema in mice. Am J Physiol Lung Cell Mol Physiol 2007        November; 293(5):L1230-L1239). Effective test compound will        significantly decrease the mean alveolar intercept length (Lm)        compared to vehicle treated PPE-exposed mice. This indicates a        marked effect of TC on lung architecture.

8. Diabetes Mellitus

Normal CD-1 mice are induced to develop hyperglycemia (diabetes) by i.v.injection with 100 mg/kg streptozotocin (STZ) followed by measurement ofblood glucose in a week. The animals are treated with test compound orvehicle daily starting the same day of STZ injection. Glucose samplesare taken from the tail vein at day 7 with Ascensia ELITE blood glucosetest strips (Bayer), and the blood glucose concentration is determinedby glucose meters (Bayer). STZ induced diabetes, as shown by asignificant increase in blood glucose levels compared to that in normalmice. Compounds of the invention reduce blood glucose levels.

9. Muscular Dystrophy.

-   -   a. In a genetic murine muscular dystrophy model, two months of        intraperitoneal administration of a compound embodied herein can        be shown to reduce the elevation in creatine kinase, indicating        a beneficial effect on the disease.

10. Amyotrophic Lateral Sclerosis.

-   -   a. In SODG93A mouse model of ALS, daily compound administration        starting at age 94 days (when neurofilament degeneration        typically occurs) through day 122 can significantly improves        hind limb pathology score vs. In addition, a stride test shows        improvement in treated animals. Survival of the treated animals        is also significantly (p<0.05) extended vs. vehicle-treated        animals.

11. Dysproliferative Diseases

-   -   a. Reduction of testosterone levels. To determine whether a        compound reduces serum testosterone levels in male mice, male        C57BL/6 mice are dosed with compound (for example: oral, 50        rag/kg) and after 4 hours, serum is collected; for comparison,        serum from male control mice that were not treated with compound        and of age-matched female mice are also obtained. Testosterone        is determined with an ELISA kit, for example from R&D Systems        (Catalog #KGR010).    -   b. Prostate cancer. To test the antineoplastic efficacy of        compounds embodied herein, nude mice carrying human prostate        cancer lines: LNCaP, VCaP or MDA-PCa-2b xenograft model will be        used. These prostate cancer cell lines LNCaP, VCap and        MDA-PCa-2b are known to express androgen receptor and have        androgen responsive growth in vitro and in vivo. Cells will be        grown in vitro in RPMI 1640 with 5% FCS and 2 million will be        inoculated in 120 μl of Matrigel (50:50 volume ratio of cells to        Matrigel). Cells will be distributed by s.c. injection at the        right and left flanks in 6 to 8 week old athymic nude mice        (BALB/c strain) or severe combined immunodeficient mice under        anesthesia. To promote hormone-dependent tumor growth in the        LNCaP model, progesterone will be administered at 50 mg/kg each        day. Tumor dimensions (length (1) and width (w)) will be        determined every 3-5 days using calipers and tumor volumes will        be calculated using the formula V=0.5236×12×w (with l>w). From        the time that xenografts reach an average volume of        approximately 100 mm³, animals will be randomized to vehicle and        treatment groups. Animals will be treated with compound for 4        weeks, at which point animals will be sacrificed and collect        blood samples and tumor tissue for the determination of serum        and tumor testosterone levels as well as serum PSA levels.        Tumors will be excised and a portion will be fixed in formalin        for subsequent histochemical and immuno-histochemical analysis.        The remainder will be snap frozen in liquid nitrogen and stored        at −80° C.        -   Serum Testosterone and PSA and Tumor Testosterone Analysis.            Tumor tissue obtained from mice will be homogenized in            phosphate buffer (pH 7.4, 0.1 M) and homogenates centrifuged            at 2000 g for 20 min. Testosterone concentrations in the            serum and in the clear tissue homogenate supernatant will be            determined with the ELISA kit from R&D Systems (Catalog            #KGR010). Serum PSA concentrations will be measured using a            PSA ELISA kit with a serum dilution according to the            manufacturers instructions.    -   c. Breast cancer. To test the efficacy of compounds embodied        herein against breast cancer, nude mice carrying human breast        cancer lines that are estrogen receptor and Aromatase positive        will be used. Cells will be grown in vitro and 2 million will be        inoculated in Matrigel (50:50 volume ratio of cells to        Matrigel). Cells will be distributed by s.c. injection at the        right and left flanks or at the orthotopic sitest in 6 to 8 week        old athymic nude mice (BALB/c strain) or severe combined        immunodeficient mice under anesthesia. Animals will be treated        with compound for 4 weeks, at which point animals will be        sacrificed and collect blood samples and tumor tissue for the        determination of serum and tumor estrogen levels. Tumors will be        excised and a portion will be fixed in formalin for subsequent        histochemical and immuno-histochemical analysis. The remainder        will be snap frozen in liquid nitrogen and stored at −80° C.    -   12. CYP26 inhibition activity. A substrate depletion assay for        ATRA metabolism in mouse microsomes is used. Mouse microsomes        are produced by Xenotech from the livers of mice treated with        ATRA for four days to induce CYP26. ATRA metabolism in these        microsomes is tested at a final concentration of 0.1 mg        protein/mL in a 100 in IN/1 phosphate buffer (pH 7.4) containing        an NADPH regenerating system (BD Biosciences catalog #451200 and        451220). The assay is run in a 100 μL reaction volume and        stopped with an equal volume of methanol. ATRA concentrations at        the beginning and end of incubations are determined using HPLC        and LC-MS/MS. The “induced” mouse microsomes have vastly        increased CYP26 transcription and ATRA metabolic activity        compared to normal microsomes (˜100 fold) and ATRA metabolic        activity displays classical Michaelis-Menten kinetics with a Km        of ˜4 nM, which is similar to the Km reported for the human        recombinant enzyme (˜10 nM).    -   13. CYP17 inhibition assay: In vitro assays for CYP17        17α-hydroxylase and C₁₇₋₂₀-lyase activity, assays using rat and        dog testis microsomes and ELISA kits from commercial vendors for        the detection of formed products are employed. Incubation of rat        testis microsomes with the substrate progesterone (P4) results,        through the CYP17 17α-hydroxylase and C17,20-lyase activities,        in a marked production of androstenedione (AD) in a time and        enzyme-concentration dependent manner. This activity can be        shown to be completely inhibited by a positive control compound,        abiraterone acetate. In another control, microsomes isolated        from rat livers, which are known to express very little or no        CYP17, are shown to be devoid of this activity. Assays are also        used that determine the activity of 17α-hydroxylase activity        using P4 as a substrate and detecting HOP4 as a product (using        dog testis microsomes) and the activity of C17,20-lyase by using        HOP4 as a substrate and AD as a product (rat testis microsomes).    -   14. CYP19 inhibition assay: For in vitro assays of CYP19        aromatase activity, commercially available CYP19 enzyme        preparations (e.g. BD Gentest Supersonics Catalog #456260) and        assay kits (e.g. BD Gentest Catalog #459520) are employed        according to the manufacturers instructions,

As detailed in the exemplification herein, in assays to determine theability of compounds to inhibit CYP26, CYP17 or CYP19 activity, certaininventive compounds exhibit IC₅₀ values≦50 μM. In certain otherembodiments, inventive compounds exhibit IC₅₀ values≦40 μM. In certainother embodiments, inventive compounds exhibit IC₅₀ values≦30 μM. Incertain other embodiments, inventive compounds exhibit IC₅₀ values≦20μM. In certain other embodiments, inventive compounds exhibit IC₅₀values≦10 μM. In certain other embodiments, inventive compounds exhibitIC₅₀ values≦7.5 μM. In certain embodiments, inventive compounds exhibitIC₅₀ values≦5 μM. In certain other embodiments, inventive compoundsexhibit IC₅₀ values≦2.5 μM. In certain embodiments, inventive compoundsexhibit IC₅₀ values≦1 μM. In certain other embodiments, inventivecompounds exhibit IC₅₀ values≦750 nM. In certain other embodiments,inventive compounds exhibit IC₅₀ values≦500 nM. In certain otherembodiments, inventive compounds exhibit IC₅₀ values≦250 nM. In certainother embodiments, inventive compounds exhibit IC₅₀ values 100 nM. Inother embodiments, exemplary compounds exhibit IC₅₀ values≦75 nM. Inother embodiments, exemplary compounds exhibit IC₅₀ values≦50 nM. Inother embodiments, exemplary compounds exhibit IC₅₀ values≦=40 nM. Inother embodiments, exemplary compounds exhibit IC₅₀ values≦30 nM. Inother embodiments, exemplary compounds exhibit IC₅₀ values≦20 nM. Inother embodiments, exemplary compounds exhibit IC₅₀ values≦10 nM. Inother embodiments, exemplary compounds exhibit IC₅₀ values≦5 nM.

Pharmaceutical Uses and Methods of Treatment In certain embodiments, themethod involves the administration of a therapeutically effective amountof the compound or a pharmaceutically acceptable derivative thereof to asubject (including, but not limited to a human or animal) in need of it.Subjects for which the benefits of the compounds of the invention areintended for administration include, in addition to humans, livestock,domesticated, zoo and companion animals.

As discussed above this invention provides novel compounds that havebiological properties useful for inhibiting CYP26, CYP 17 or CYP19activity and reducing fibrosis or dysproliferative conditions. Incertain embodiments, the inventive compounds are useful for thetreatment of wounds for acceleration of healing (wound healing may beaccelerated by promoting cellular proliferation, particularly ofvascular cells), normalization of myocardial perfusion as a consequenceof chronic cardiac ischemia or myocardial infarction, development oraugmentation of collateral vessel development after vascular occlusionor to ischemic tissues or organs, fibrotic diseases, hepatic diseaseincluding fibrosis and cirrhosis, lung fibrosis, renal failure, renalfibrosis, cerebral infarction (stroke), diabetes mellitus, andvascularization of grafted or transplanted tissues or organs. Renalconditions for which compounds of the invention may prove usefulinclude: radiocontrast nephropathy; fibrosis secondary to renalobstruction; indication for renal trauma and transplantation; renalfailure secondary to chronic diabetes and/or hypertension. Benefit intreatment of amyotrophic lateral sclerosis, diabetes mellitus andmuscular dystrophy are also embodied herein. Furthermore, benefits indysproliferative diseases such as cancer, inflammatory skin diseases,psoriasis, inflammatory joint diseases, among others, are also provided.

Furthermore, after formulation with an appropriate pharmaceuticallyacceptable carrier in a desired dosage, the pharmaceutical compositionsof this invention can be administered to humans and other animalsorally, rectally, parenterally, intracistemally, intravaginally,intraperitoneally, subcutaneously, intradermally, intra-ocularly,topically (as by powders, ointments, or drops), buccally, as an oral ornasal spray, or the like, depending on the severity of the disease ordisorder being treated. In certain embodiments, the compounds of theinvention may be administered at dosage levels of about 0.001 mg/kg toabout 50 mg/kg, preferably from about 0.1 mg/kg to about 10 mg/kg forparenteral administration, or preferably from about 1 mg/kg to about 50mg/kg, more preferably from about 10 mg/kg to about 50 mg/kg for oraladministration, of subject body weight per day, one or more times a day,to obtain the desired therapeutic effect. It will also be appreciatedthat dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (forexample 50-100 mg/kg) can be administered to a subject. In certainembodiments, compounds are administered orally or parenterally.

Moreover, pharmaceutical compositions comprising one or more compoundsof the invention may also contain other compounds or agents for whichco-administration with the compound(s) of the invention istherapeutically advantageous. As many pharmaceutical agents are used inthe treatment of the diseases and disorders for which the compounds ofthe invention are also beneficial, any may be formulated together foradministration. Synergistic formulations are also embraced herein, wherethe combination of at least one compound of the invention and at leastone other compounds act more beneficially than when each is given alone.Non-limiting examples of pharmaceutical agents that may be combinedtherapeutically with compounds of the invention include (non-limitingexamples of diseases or conditions treated with such combination areindicated in parentheses): antivirals and antifibrotics, such asinterferon alpha (hepatitis B, and hepatitis C), combination ofinterferon alpha and ribavirin (hepatitis C), Lamivudine (hepatitis B),Adefovir dipivoxil (hepatitis B), interferon gamma (idiopathic pulmonaryfibrosis, liver fibrosis, and fibrosis in other organs); anticoagulants,e.g., heparin and warfarin (ischemic stroke); antiplatelets e.g.,aspirin, ticlopidine and clopidogrel (ischemic stroke); other growthfactors involved in regeneration, e.g., VEGF and FGF and mimetics ofthese growth factors; antiapoptotic agents; and motility and morphogenicagents. All-trans retinoic acid and active analogs are also provided ascombination therapy.

Treatment Kit

In other embodiments, the present invention relates to a kit forconveniently and effectively carrying out the methods in accordance withthe present invention. In general, the pharmaceutical pack or kitcomprises one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. Suchkits are especially suited for the delivery of solid oral forms such astablets or capsules. Such a kit preferably includes a number of unitdosages, and may also include a card having the dosages oriented in theorder of their intended use. If desired, a memory aid can be provided,for example in the form of numbers, letters, or other markings or with acalendar insert, designating the days in the treatment schedule in whichthe dosages can be administered. Alternatively, placebo dosages, orcalcium dietary supplements, either in a form similar to or distinctfrom the dosages of the pharmaceutical compositions, can be included toprovide a kit in which a dosage is taken every day. Optionallyassociated with such container(s) can be a notice in the form prescribedby a governmental agency regulating the manufacture, use or sale ofpharmaceutical products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

EQUIVALENTS

The representative examples that follow are intended to help illustratethe invention, and are not intended to, nor should they be construed to,limit the scope of the invention. Indeed, various modifications of theinvention and many further embodiments thereof, in addition to thoseshown and described herein, will become apparent to those skilled in theart from the full contents of this document, including the exampleswhich follow and the references to the scientific and patent literaturecited herein. It should further be appreciated that the contents ofthose cited references are incorporated herein by reference to helpillustrate the state of the art.

The following examples contain important additional information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and the equivalents thereof.

EXEMPLIFICATION

The compounds of this invention and their preparation can be understoodfurther by the examples that illustrate some of the processes by whichthese compounds are prepared or used. It will be appreciated, however,that these examples do not limit the invention. Variations of theinvention, now known or further developed, are considered to fall withinthe scope of the present invention as described herein and ashereinafter claimed.

1) General Description of Synthetic Methods:

The practitioner has a well-established literature of small moleculechemistry to draw upon, in combination with the information containedherein, for guidance on synthetic strategies, protecting groups, andother materials and methods useful for the synthesis of the compounds ofthis invention.

The various references cited herein provide helpful backgroundinformation on preparing compounds similar to the inventive compoundsdescribed herein or relevant intermediates, as well as information onformulation, uses, and administration of such compounds which may be ofinterest.

Moreover, the practitioner is directed to the specific guidance andexamples provided in this document relating to various exemplarycompounds and intermediates thereof.

The compounds of this invention and their preparation can be understoodfurther by the examples that illustrate some of the processes by whichthese compounds are prepared or used. It will be appreciated, however,that these examples do not limit the invention. Variations of theinvention, now known or further developed, are considered to fall withinthe scope of the present invention as described herein and ashereinafter claimed.

According to the present invention, any available techniques can be usedto make or prepare the inventive compounds or compositions includingthem. For example, a variety of solution phase synthetic methods such asthose discussed in detail below may be used. Alternatively oradditionally, the inventive compounds may be prepared using any of avariety of combinatorial techniques, parallel synthesis and/or solidphase synthetic methods known in the art.

It will be appreciated as described below, that a variety of inventivecompounds can be synthesized according to the methods described herein.The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCompany (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis,Mo.), or are prepared by methods well known to a person of ordinaryskill in the art following procedures described in such references asFieser and Fieser 1991, “Reagents for Organic Synthesis”, vols 1-17,John Wiley and Sons, New York, N.Y., 1991; Rodd 1989 “Chemistry ofCarbon Compounds”, vols. 1-5 and supps, Elsevier Science Publishers,1989; “Organic Reactions”, vols 1-40, John Wiley and Sons, New York,N.Y., 1991; March 2001, “Advanced Organic Chemistry”, 5th ed. John Wileyand Sons, New York, N.Y.; and Larock 1990, “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations”, 2^(nd) ed.NTH Publishers. These schemes are merely illustrative of some methods bywhich the compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to aperson of ordinary skill in the art having regard to this disclosure.

The starting materials, intermediates, and compounds of this inventionmay be isolated and purified using conventional techniques, includingfiltration, distillation, crystallization, chromatography, and the like.They may be characterized using conventional methods, including physicalconstants and spectral data.

General Reaction Procedures:

Unless mentioned specifically, reaction mixtures are stirred using amagnetically driven stirrer bar. An inert atmosphere refers to eitherdry argon or dry nitrogen. Reactions are monitored either by thin layerchromatography, by proton nuclear magnetic resonance (NMR) or byhigh-pressure liquid chromatography (HPLC), of a suitably worked upsample of the reaction mixture.

General Work Up Procedures:

Unless mentioned specifically, reaction mixtures are cooled to roomtemperature or below then quenched, when necessary, with either water ora saturated aqueous solution of ammonium chloride. Desired products areextracted by partitioning between water and a suitable water-immisciblesolvent (e.g. ethyl acetate, dichloromethane, diethyl ether). Thedesired product containing extracts are washed appropriately with waterfollowed by a saturated solution of brine. On occasions where theproduct containing extract is deemed to contain residual oxidants, theextract is washed with a 10% solution of sodium sulphite in saturatedaqueous sodium bicarbonate solution, prior to the aforementioned washingprocedure. On occasions where the product containing extract is deemedto contain residual acids, the extract is washed with saturated aqueoussodium bicarbonate solution, prior to the aforementioned washingprocedure (except in those cases where the desired product itself hadacidic character). On occasions where the product containing extract isdeemed to contain residual bases, the extract is washed with 10% aqueouscitric acid solution, prior to the aforementioned washing procedure(except in those cases where the desired product itself had basiccharacter). Post washing, the desired product containing extracts aredried over anhydrous magnesium sulphate, and then filtered. The crudeproducts are then isolated by removal of solvent(s) by rotaryevaporation under reduced pressure, at an appropriate temperature(generally less than 45° C.).

General Purification Procedures:

Unless mentioned specifically, chromatographic purification refers toflash column chromatography on silica, using a single solvent or mixedsolvent as eluent. Suitably purified desired product containing elutesare combined and concentrated under reduced pressure at an appropriatetemperature (generally less than 45° C.) to constant mass.

1) Synthesis of Exemplary Compounds:

Unless otherwise indicated, starting materials are either commerciallyavailable or readily accessibly through laboratory synthesis by anyonereasonably familiar with the art. Described generally below, areprocedures and general guidance for the synthesis of compounds asdescribed generally and in subclasses and species herein. In addition,synthetic guidance can be found in Kinoshita, M. et al. Bull. Chem. Soc.Jpn. 1987, 60, 2151-2162; Natchev, I. A. Tetrahedron 1988, 44,1511-1522; Almirante, N. et al. Tetrahedron Lett. 1998, 39, 3287; andBeliassoued and Majidi, J. Org. Chem., 1993, 58, 2517-2522; the entirecontents of which are hereby incorporated by reference.

Moreover, guidance for the synthesis of the compounds embodied hereinmay be found in Bioorganic 8r, Medicinal Chemistry 15 (2007) 3692-3702;ARKIVOC 2007 (viii) 150-154; J. Med. Chem. 784, 1970; J. Org. Chem.2008, 73, 538-549; Synth. Commun. Vol. 32, No. 22. pp. 3399-3405, 2002;J. Org. Chem., 2007, 72, 8543-8546; J. Org. Chem., 2001, 66, 7945-7950;J. Med. Chem. 2007, 50, 6116-6125; 5. Org. Chem. 1993, 58, 7899-7902;Tetrahedron, Vol. 53, No. 33, pp. 11355-11368, 1997; Synthesis 2006, No.6, 995-998; Tetrahedron Letters 39 (1998) 9347-9350; Synthesis-1986,620; US patents/applications 0208582; U.S. Pat. No. 3,050,520; U.S. Pat.No. 4,625,036; U.S. Pat. No. 7,192,976; U.S. Pat. No. 7,250,437; U.S.Pat. No. 7,265,112; WO 2005/073189 or WO2004/058721, Other sourcesinclude WO2005/007631, based on PCT/US2004/022282, and in WO2002/03912,based on PCT/US2001/16524.

Synthesis of Exemplary Compounds Example-16-(2-(Dimethylamino)-1-(1H-imidazol-yl)butyl)benzo[d]thiazol-2-amine

Step-1: A flask was charged with 4-amino-phenylbutanone (4.0 g, 24.5mmol), acetic anhydride (2.77 mL, 29.4 mmol), TEA (5.17 mL. 36.8 mmol)and DMAP (300 mg, 2.45 mmol) in 100 mL DCM. The reaction was stirred atrt for 48 hr. The mixture was partitioned between DCM and saturatedNaHCO₃. The aqueous phase was extracted once with DCM and the combinedorganic extracts were washed with brine and then dried over anhydrousNa₂SO₄. The extracts were concentrated in vacuo, adsorbed onto silicaact and purified by column chromatography eluting with 60%EtOAc/hexanes. Product containing fractions were combined andconcentrated in vacuo to provide N-(4-butyrylphenyl)acetamide. MS ESI:m/z 206.14 [M+1⁺].

Step-2: A solution of N-(4-butyryl-phenyl)acetamide (3.47 g, 16.9 mmol)in 100 mL of anhydrous DCM was cooled to 0° C. under N, and treated withA1Cl₃ (180 mg, 1.35 mmol). Approximately 10 mL of Br₂ was added and themixture was stirred for 10 min. The reactor was removed from the coolingbath and the remaining Br₂ was added dropwise via syringe over 0.5 min.After 3 hr, the dark orange color of Br₂ had faded and by 3¼ hr aprecipitate had formed. The reaction was quenched with saturated NaHCO₃.The phases were separated and the aqueous phase extracted three timeswith DCM. The combined extracts were dried over Na₂SO₄, filtered througha Celite® pad and concentrated in vacuo to giveN-(4-(2-bromobutanoyl)phenyl)acetamide which was used withoutpurification. MS ESI: m/z 284.10 [M⁺].

Alternate Preparation of N-(4-(2-bromobutanoyl)phenyl)acetamide

A suspension of CuBr₂ (1.14 g, 4.87 mmol) in 2.5 mL of EtOAc was heatedto reflux and treated with a suspension of N-(4-butyrylphenyl)acetamide(500 mg, 2.44 mmol) in 3.0 mL of CHCl₃. An additional 5 mL of CHCl₃ plus3.5 mL of EtOAc was required to dissolve all the acetophenone. After 3hr at reflux, the mixture was allowed to cool to rt and was filteredthrough Celite®. The filtrate was concentrated in vacuo and the residuewas partitioned between EtOAc and half-saturated NaHCO₃. The aqueousphase was extracted once with EtOAc and the combined organics were driedover Na₂SO₄, decanted and concentrated in vacuo. After adsorbing untosilica gel, the material was purified by column chromatography elutingwith 50-60% EtOAc/hexanes. Product containing fractions were combinedand concentrated in vacuo to provide the desired product as an oil thatsolidified upon standing.

Step-3: A solution of N-(4-(2-bromobutanoyl)phenyl)acetamide (4.80 g,16.9 mmol) in 30 mL CHCl₃ and 30 mL MeOH was treated with 16.9 mLdimethylamine in MeOH (2M, 33.8 mmol) and DIPEA (2.90 mL, 16.9 mmol).After stirring at it for 48 hr, the mixture was concentrated in vacuoand the residue partitioned between DCM and saturated NaHCO₃. Theaqueous phase was extracted with DCM three times. The combined organicextracts were dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography eluting with 6% MeOH (2NNH₃)/DCM to provide N-(4-(2-(dimethylamino)butanoyl)phenyl)acetamide asa light brown oil. MS ESI: m/z 249.19 [M+1⁺].

Step-4: A solution of N-(4-(2-(dimethylamino)butanoyl)phenyl)acetamide(3.80 g, 15.30 mmol) in 40 mL MeOH was cooled in an ice bath under N₂and treated with NaBH₄ (725 mg, 19.12 mmol), added in one portion. Thereaction vessel was removed from the ice bath and stirred at rt over theweekend. The reaction was quenched with acetone, then concentrated invacuo and partitioned between DCM and half-saturated NaHCO₃. The aqueousphase was extracted four times with DCM and the organic extracts werecombined and dried over Na₂SO₄. The solution was decanted andconcentrated in vacuo. The solid residue was purified by silica gelcolumn chromatography eluting with 10%-12% MeOH (2N NH₃)/DCM to providethe syn-isomer ofN-(4-(2-(dimethylamino)-1-hydroxybutyl)phenyl)acetamide as a whiteamorphous solid and the anti-isomer as a straw colored oil. MS ESI: m/z251.17 [M+1⁺].

Step-5: A solution ofN-(4-(2-(dimethylamino)-1-hydroxybutyl)phenyl)acetamide (3.0 g, 12.0mmol) in 50 mL of acetonitrile was treated with carbonyldiimidazole(2.53 g, 15.58 mmol) and heated at reflux overnight. The solution wasconcentrated in vacuo and the residue partitioned between half saturatedNaHCO₃ and DCM. The aqueous phase was extracted with DCM three times.The combined organic extracts were dried over Na₂SO₄, decanted andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 8% MeOH (2N NH₃)/DCM to giveN-(4-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)phenyl)acetamide. MSESI: m/z 301.19 [M+1⁺].

Step-6: A solution of N-(4-(2-(dimethylamino1-(H-imidazol-1-yl)butyl)phenyl)acetamide (2.95 g, 9.82 mmol) in 50 mLof 3N HCl (was heated at 60° C. overnight. After cooling to rt, thesolution was poured onto ice and basified with 6N NaOH. This wasextracted with DCM (4×100 mL). The combined organic extracts were driedover Na₂SO₄, decanted and concentrated in vacuo. The crude4-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)aniline was used withoutfurther purification. MS ESI: m/z 259.19 [M+1⁺].

Step-7: A solution of4-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)aniline (600 mg, 2.32mmol) and KSCN (508 mg, 5.22 mmol) in 15 mL AcOH was cooled to about 7°C. and treated with Br₂ (125 μL, 2.43 mmol) in 2 mL AcOH added drop-wisevia syringe over 5 min. The reaction vessel was removed from the coolingbath and stirred at rt for 1 hr. The reaction was cooled in an ice bathand basified with 3N NaOH (100 mL) added portionwise over severalminutes. This mixture was then extracted with DCM (4×75 mL). Thecombined organic extracts were dried over Na₂SO₄, decanted andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 6% MeOH (2N NH₃)/DCM to give6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amineas a yellow foam. MS ESI: m/z 316.16 [M+1⁺].

Example-21-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea

A mixture of6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine(50 mg, 0.151 mmol) and carbonyldiimidazole (50 mg, 30 mmol) in DCM wasstirred at RT for 5 h. Aqueous ammonia was added and the reaction wasstirred over night. The reaction was diluted with water and extractedwith DCM. The combined organic extracts were dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by preparative TLC toafford1-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea.MS ESL m/z 359.27 [M+1⁺].

Example-3 Ethyl(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamate

A solution of6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine(52 mg, 0.16 mmol) and Hunig's base (31.6 μL, 0.18 mmol) in DCM (1 mL)was treated with ethyl chloroformate (17.3 μL, 0.0.18 mmol) in 2 mL 10%AcOH THF. The mixture was stirred at room temperature overnight. Thesolution was concentrated in vacuo and the residue was purified usingPTLC on a 1 mm silica plate eluting with 5% MeOH (2N NH₃)/DCM to provideEthyl(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamate.MS (ESI⁺) m/z 388.17 [M+H]⁺

Example-4 Ethyl3-(((6-(2-(dimethylamino)-(1H-pyrrol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate

A solution of1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine(25 mg, 0.08 mmol) and methyl 4-formylbenzoate (13 mg, 0.08 mmol) in 2mL toluene, along with some 4 Å molecular sieves was heated in a sealedtube at 100° C. overnight. After cooling to 60° C., sodium borohydride(6 mg, 0.16 mmol) in 2 mL ethanol was added and the mixture was againheated to 100° C. After about 40 hr, TLC indicated consumption of thestarting aldehyde. The mixture was filtered, concentrated in vacuo andthe residue purified by PTLC using a 2 mm silica plate eluting with 5%MeOH (2N NH₃)/DCM to provide ethyl3-(((6-(2-(dimethylamino)-1-(1H-pyrrol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate.MS (ESI⁺) m/z 478.26 [M+H]⁺

Example-5 Methyl3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]-thiazol-2-yl)amino)methyl)benzoate;and Example-6 Isopropyl3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]-thiazol-2-yl)amino)methyl)benzoate

A mixture of6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine(25 mg, 0.079 mmol), Ti(i-OPr)₄ (50 μL, 0.158 mmol), andmethyl-3-formyl-benzoate (26 mg 0.158 mmol) was stirred together at rtin 2 mL THE overnight. Afterwards, NaBH₄ (6.0 mg, 0.158 mmol) was addedand the mixture was stirred at rt for 1 hr. The reaction was quenchedwith acetone, concentrated in vacuo and the residue was purified byprep-TLC using 3 1 mm plates eluting with 7% MeOH (2N NH₃)/DCM toprovide the product as a mixture of methyl3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]-thiazol-2-yl)amino)methyl)benzoate,MS ESI: m/z 464.23 [M+H]⁺; and isopropyl3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]-thiazol-2-yl)amino)methyl)benzoate,MS (ESI⁺) m/z 492.24 [M+H]⁺.

Example 73-(((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid

A solution of methyl3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]-thiazol-2-yl)amino)methyl)benzoate(18 mg, 0.037 mmol) in 500 μL THF was treated with LiOH (10 mg, 0.238mmol, 6.5 equiv) in 500 μL water. This was heated at 50° C. overnight.Afterwards the reaction was neutralized with 240 μL of 1N HCl andconcentrated in vacuo. The residue was purified by prep-TLC using a 1 mmsilica, plate eluting twice with 20% MeOH/DCM to provide3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid. MS ESI: m/z 462.21 [M−1⁺].

Example-81-(2-Bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine

To a mixture of6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine(4.75 g, 15.06 mmol) and water (46 mL) at 0° C. was added aqueous HBr(18.5 mL) and the mixture was cooled to −10° C. A cold (−10° C.)solution of sodium nitrite (1.3 g) in water (15 mL) was added to thereaction mixture over a period of 10 min while maintaining thetemperature below −5° C. and the reaction was stirred at −10° C. for 15min. To the reaction mixture was added a cold (−10° C.) solution ofCuBr₂ in water (46 mL), cooling bath was removed and stirred for 3 h.The reaction was basified using aqueous sodium carbonate, filteredthrough a pad of celite and extracted with DCM. The DCM extract waswashed with water, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography using 0 to 2%methanol in DCM as eluent to afford1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine.MS ESI: m/z 400.9 [M+Na⁺].

Example-9N-(6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide

A mixture of6-(2-(ethylmethyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine(50 mg, 0.151 mmol) and acetic anhydride (37 mg, 0.37 mmol) in THF (4mL) was stirred at 40° C. over 3 days. The reaction was quenched withsaturated sodium carbonate, extracted with 5% methanol in DCM. Thecombined organic extracts were dried over Na₂SO₄, and concentrated invacuo. The residue was purified by preparative TLC to affordN-(6-(2-(ethyl(methyl)amino)-1-H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide.MS ESI: m/z 372.28 [M+1⁺].

Example-101-(2-Chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine

A mixture of1-(2-bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine(5 mg, 0.1 mmol) and 2N HCl (5 in L) was stirred at Rt for 1 h. Themixture was filtered and evaporated to afford1-(2-chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine.MS ESI: m/z 349.2 [M+H⁺].

Example-116-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylicacid

To a solution of1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine(76 mg, 0.2 mmol) in THF (10 mL) at −78° C. was added t-BuLi (0.24 mL,1.7 M solution) and the reaction was stirred for 15 min. Dry CO₂ wasbubbled for 1 h while allowing the reaction to warm to 0° C. Water wasadded and extracted with DCM. The water layer was neutralized andevaporated. The residue was extracted with methanol to afford6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylicacid. MS ESI: m/Z 345.26 [M+H⁺].

Example-12 Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylateExample-13 Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carbimidateExample-146-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxamide;and Example-151-(Benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine

A degassed mixture of1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine(76 mg, 0.2 mmol), Pd₂(dba)₃ (36.6 mg, 0.04 mmol), dppf (53 mg, 0.048mmol) and zinc cyanide (14.1 mg, 0.06 mmol) in DMf (2 mL) and water(0.05 mL) under nitrogen was stirred at 110° C. overnight. DMF wasevaporated under reduced pressure and the residue was extracted withmethanol. The methanol extract was evaporated and the residue waspurified multiple times by preparative TLC to afford methyl 6-(2-(dimeylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylate. MSESI: m/z 359.26 [M+H⁺]; methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carbimidate.MS ESI: m/z 358.17 [M+H⁺];6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxamide.MS ESI: m/z 344.23 [M+H⁺]; and1-(benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine.MS ESI: m/z 301.25 [M+H⁺].

Example 16Methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate

A solution of1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine(30 mg, 0.079 mmol), methyl-4-aminobenzoate (24 mg, 0.16 mmol) in 300 μLDCE and 300 μL n-BuOH was treated with 4N HCl (40 μL, 0.16 mmol) andrefluxed overnight. The mixture was then partitioned between DCM andsaturated NaHCO₃ and the aqueous phase was extracted with DCM. Thecombined organic extracts were dried over Na₂SO₄, decanted andconcentrated in vacuo. The residue was purified by PTLC using two 1 mmsilica plates eluting with 5% MeOH (2N NH₃)/DCM to providemethyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate.MS (ESI⁺) nil 450.19 [M+H]⁺.

Example-174-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicacid

A mixture ofmethyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)amino)benzoate(46 mg, 0.10 mmol) and lithium hydroxide monohydrate (21 mg, 0.51 mmol)in 4 mL of dioxane and 2 mL of water was heated together with stirringat 50° C. for 4 hr. The mixture was concentrated in vacuo and theresidue dissolved in about 2 mL of water. The solution was neutralizedwith 1N HCl then concentrated again in vacuo. The residue was purifiedby PTLC using two, 2 mm silica plates eluting with 20% MeOH/DCM to give4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicacid. MS (ESI⁺) m/z 436.22 [M+H]⁺

Example-18 Isopropyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoate

Step-1: A solution of methyl 3-hydroxy-2,2-dimethylpropanoate (8.6 g,65.1 mmol) in 100 mL DCM was cooled to 0° C. under N₂. PCC (24.8 g,115.2 mmol) was added portionwise over several minutes. The mixture wasallowed to gradually warm to room temperature and was stirred overnight.The mixture was filtered through silica gel. Enough Celite is added tothe remaining oil so that all is adsorbed. This is added to the top of asilica pad and this is washed with about 1.5 L DCM. The solution is thencarefully concentrated in vacuo, maintaining the water bath at about 30°C. to obtain methyl 2,2-dimethyl-3-oxopropanoate as a clear colorlessoil. ¹H (300 MHz, CDCl₃, δ) 9.60 (s, 1H), 3.70 (s, 3H), 1.29 (s, 6H).

Step 2. A mixture of6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine(32 mg, 0.10 mmol), methyl 2,2-dimethyl-3-oxopropanoate (26 mg, 0.20mmol) and titanium isoproxide (60 mL, 0.20 mmol) was stirred together in400 μL THF at room temperature for 72 hr. Sodium borohydride (8 mg, 0.20mmol) in 300 μL. MeOH was added and the solution was stirred at roomtemperature overnight. The reaction was quenched with acetone andconcentrated in vacuo. The DCM soluble components were applied to two, 1mm silica PTLC plates, which were developed in 8% MeOH (2 N NH3)/DCM toprovide isopropyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoate,MS (ESI⁺) m/z 458.17 [M+H]⁺

Example-193-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoicacid

A mixture isopropyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoate(30 mg, 0.065 mmol) in 300 μL dioxane and 300 μL water was treated withlithium hydroxide monohydrate (21.4 mg, 0.57 mmol) and heated at 100 for1 hr. The mixture was concentrated in vacuo and the residue dissolved inabout 2 mL of water. The solution was neutralized with 1N HCl thenconcentrated again in mew). The residue was purified by PTLC using two,1 mm silica, plates eluting with 10% MeOH/DCM to give the titlecompounds. MS (ESI⁻) m/z 414.98 [M−H]⁻

Example 204-((6-(2-dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-4-oxobutanoicacid

A mixture of 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butylbenzo[d]thiazol-2-amine (16 mg, 0.05 mmol) and3,3-dimethyldihydrofuran-2(3H)-one (6.5 mg, 0.05 mmol) in DCM wasstirred for 5 h at RT. The reaction mixture was evaporated and theresidue was purified by PTLC using 10% methanol in DCM as eluent toafford4-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-4-oxobutanoicacid. MS ESI: m/z 442.14 [M−1⁻].

Example 21 Methyl4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate

A mixture of 4-(methoxycarbonyl)benzoic acid (18 mg, 0.1 mmol), HATU(41.8 mg, 0.11 mmol), and diisopropylethylamine (39 mg) in DMF wasstirred at RT for 5 min. A syn and anti mixture of6-(2-(dimethylamino)-1-(1H-Imidazol-1-yl)butyl)benzo[d]thiazol-2-amine(31.5 mg, 0.1 mmol) in DMF was added and stirred at RT. DMF wasevaporated and the residue was purified by PTLC using 10% methanol inDCM as eluent to afford the syn and anti isomers of methyl4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate.ESI: m/z 478.2 [M+1⁺].

Example 224-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid

A mixture of methyl4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate(15 mg, 0.031 mmol) and lithium hydroxide (6.6 mg, 0.157 mmol) indioxane (2 mL) and water (1 mL) was stirred at 50° C. for 4 h. Thereaction was evaporated, water was added and neutralized to pH 7. Theslurry obtained was evaporated and extracted with DCM-methanol mixtureand evaporated. The crude acid was purified by PTLC using DCM-methanolmixture as eluent to afford4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid. MS ESI: m/462.11 [M−1⁻].

Example-23 Methyl4-((6-(2-(dimethylamino-1-(1H-1-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate

A suspension of1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine(54 mg, 0.14 mmol), methyl-4-hydroxybenzoate (21.7 mg, 0.14 mmol) andpotassium carbonate (21.6 mg, 0.16 mmol) in 1 mL of DMF was heated at80° C. overnight. The mixture was concentration in vacuo and the residuepartitioned between water and DCM. After extracting the aqueous layer,the combined DCM extracts were dried over Na₂SO₄, decanted andconcentrated in vacuo. The residue was purified using PTLC and elutingwith 5% MeOH (2N NH₃)/DCM to providemethyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate.MS (ESI) m/z 451.17 [M+H]⁺.

Example-244-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoicacid

A mixture ofmethyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)oxy)benzoate(65 mg, 0.14 mmol) and lithium hydroxide monohydrate (30 mg, 0.72 mmol)in 4 mL of dioxane and 2 mL of water was heated together with stirringat 50° C. for 4 hr. The mixture was concentrated in vacuo and theresidue dissolved in about 2 mL of water. The solution was neutralizedwith 1N HCl then concentrated again in vacuo. The residue was purifiedby PTLC using two, 2 mm silica plates eluting with 20% MeOH/DCM to givethe title compound. MS (ESI⁺) m/z 437.21 [M+H]⁺.

Example-25 Methyl4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate

A mixture of1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine(663 mg, 1.75 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (409 mg,2.275 mmol), tetrakis(triphenylphosphine)palladium (505 mg, 0.437 mmol),potassium carbonate (725 mg, 5.25 mmol); DME (25 mL) and water (5 mL)was degassed, filled with N₂, and heated to 80° C. for 3 h. The reactionmixture was evaporated, dissolved in 10% methanol in DCM, loaded onto aPTLC plate and eluted with 6% methanol in DCM to yield methyl4-(6-(2-(dimethylamino)-1-(1H-imidazo1-yl)butyl)benzo[d]thiazol-2-yl)benzoate. MS ESI: m/z 435.19 [M+1⁺].

Example-264-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid

A mixture of methyl4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate(115 mg, 0.265 mmol) and LiOH (31.7 mg, 1.33 mmol) in water (1.5 mL) anddioxane was heated to 50° C. and stirred for 2 h. The solvent wasevaporated, water was added and neutralized to pH 7 and evaporated. Theresidue was dissolved in 35% methanol in DCM, loaded onto a PTLC plateand eluted with 30% methanol in DCM. To afford4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid. MS ESI: m/z 421.17 [M+1⁺].

Example-27 6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine

Step 1: To a solution of N-(4-butyrylphenyl)acetamide (3 g, 14.6 mmol)in THF (300 mL) was added 2.0 M LDA THF (18.3 mL) at −78° C. and thenthe reaction mixture was stirred for 1 h at −78° C. Iodoethane was addedand stirred overnight at RT. The reaction mixture was quenched with sat.aq. NH₄Cl and then extracted with ethyl acetate. The combined organiclayers were dried over MgSO₄, filtered and then concentrated. The crudeproduct was purified by preparative TLC using 50% ethyl acetate inhexane as eluent to afford N-(4-(2-ethylbutanoyl)phenyl)acetamide aswhite solid. MS (ES+): m/z 234.28 (MH⁺).

Step 2: A solution of N-(4-(2-ethylbutanoyl)phenyl)acetamide (730 mg,3.13 mmol) in MeOH (20 mL) was cooled in an ice bath under N₂ andtreated with NaBH₄ (148 mg, 3.91 mmol), added in one portion. Thereaction vessel was removed from the ice bath and stirred overnight atRT. The reaction was concentrated and partitioned between DCM andhalf-saturated NaHCO₃. The aqueous phase was extracted four times withDCM and the organic extracts were combined and dried over MgSO₄,filtered and then concentrated. The crude product was purified bypreparative TLC using 50% ethyl acetate in hexane as eluent to affordN-(4-(2-ethyl-1-hydroxybutyl)phenyl)acetamide as white solid. MS (ES+):m/z 236.24 (MH⁺).

Step 3: A solution of N-(4-(2-ethyl-1-hydroxybutyl)phenyl)acetamide (690mg, 2.93 mmol) in acetonitrile (22 mL) was treated withcarbonyldiimidazole (618 mg, 3.81 mmol) and stirred at RT over theweekend. The solution was concentrated in vacuo and the residue waspartitioned between water and ethyl acetate. The organic extract wasdried over MaSO₄, filtered and then concentrated. The crude product waspurified by preparative TLC using 5 MeOH in DCM as eluent to afford toN-(4-(2-ethyl-1-(1H-imidazol-1-yl)butyl)phenyl)acetamide as white solid.MS (ES+): m/z 286.30 (MH⁺).

Step 4: A solution ofN-(4-(2-ethyl-1-(1H-imidazol-1-yl)butyl)phenyl)acetamide (350 mg, 1.23mmol) in 3N HCl (3.28 mL) was stirred overnight at 60° C. After coolingto room temperature, the solution was poured onto ice and basified with6N NaOH (pH=12-14). The aqueous phase was extracted three times with DCMand the organic extracts were combined and dried over MgSO₄, filteredand then concentrated to afford to4-(2-ethyl-1-(1H-imidazol-1-yl)butyl)aniline, MS (ES+): m/z 244.31(MH⁺).

Step 5: A solution of 4-(2-ethyl-1-(1H-imidazol-1-yl)butyl)aniline (285mg, 1.17 mmol) and KSCN (455 rug, 4.68 mmol) in AcOH (6 mL) was stirreduntil all dissolved at RT and then treated with Br₂ (0.063 mL, 1.23mmol) in AcOH (2 mL) added drop wise via syringe over 5 min. Thereaction mixture was stirred overnight at RT. The reaction mixture wasdiluted with ice water and then basified with NH₄OH (pH 12). The aqueousphase was extracted three times with DCM and the organic extracts werecombined and dried over filtered and then concentrated. The crudeproduct was purified by preparative TLC using 5% MeOH in DCM as eluentto afford to6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine as paleyellow solid. MS (ES+): 301.27 (MH⁺).

Example-28 2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole

To a solution of6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (260 mg,0.866 mmol) and water (4 mL) at 0° C. was added aqueous HBr (0.98 mL,8.66 mmol) and the mixture was cooled to −0° C. A cold (−10° C.)solution of sodium nitrite (75 mg, 1.08 mmol) in water (1 mL) was addedto the reaction mixture over a period of 5 min while maintaining thetemperature below −5° C. and the reaction was stirred at −10° C. for 15min. To a cold (−10° C.) solution of CuBr₂ (253 mg, 1.08 mmol) in water(4 mL) was added the reaction mixture and stirred for 10 min at 0° C.MeCN was added to the reaction mixture and then the reaction mixture wasstirred for 2.5 h while warming to RT. The reaction was basified withsat. aq. NaHCO₃ (pH 7) and then 10 N NaOH (pH 8) followed by celitefiltration. The aqueous phase was extracted three times with DCM and theorganic extracts were combined and dried over MgSO₄, filtered and thenconcentrated. The crude product was purified by preparative TLC using 5%MeOH in DCM as eluent to afford to2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole as whitesolid. MS (ES+): m/z 364 (MH⁺).

Example-29 Methyl4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate

A solution of2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole (93 mg,0.255 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (50.6 mg, 0.281mmol), tetrakis(triphenylphosphine)palladium (29.5 mg, 0.0255 mmol),potassium carbonate (106 mg, 0.765 mmol), DME (5 mL) and water (0.8 mL)was degassed, filled with N₂, and heated to 80° C. for 6 h. The reactionmixture was evaporated. The crude product was purified by columnchromatography using 5 MeOH in DCM as eluent to afford to methyl4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-1-yl)benzoate aswhite solid. MS (ES+): m/z 420.28 (MH⁺).

Example-304-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid

A solution of methyl4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate(74 mg, 0.176 mmol) and LiOH (37 mg, 0.882 mmol) in water (1.5 mL) anddioxane (3 mL) was heated to 50° C. and stirred overnight. The solventwas evaporated, water was added and neutralized to pH 7 using 1 N HCland evaporated. The crude product was purified by preparative TLC using30% MeOH in DCM as eluent to afford to4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid as white solid. MS (ES+): m/z 406.28 (MH⁺).

Example-31 Methyl4-(6-(1-(1H-1,2,4-triazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate

Step-1: To a mixture of 4-butylaniline 67 mmol) and KSCN (26 g, 268mmol) in acetic acid was added Br₂ in acetic acid (70 mL) dropwise over6 min at RT. The mixture was stirred at RT overnight and poured intowater (2 L). The precipitate was collected, washed with water and driedto afford 6-butylbenzo[d]thiazol-2-amine. MS (ESI⁺) m/z 207.20 [M+H]⁺

Step-2: To a solution of 6-butylbenzo[d]thiazol-2-amine (10 g, 48.5mmol) and CuBr₂ (17 g, 73.7 mmol) in acetonitrile (500 mL) was addedt-BuONO (7.5 g, 73.7 mmol) at 0° C. over 5 min. The reaction was allowedto warm to RT and stirred overnight. Acetonitrile was evaporated. Theresidue was extracted with ethyl acetate, washed with 6N HCl, water, aq.sodium bicarbonate and brine, dried over anhydrous sodium sulfate andconcentrated. The crude product was purified by column chromatographyover silica gel using hexane as eluent to afford2-bromo-6-butylbenzo[d]thiazole as light brown oil. MS (ESL) m/z 272.1[M+2]⁺.

Step-3: To a solution of 2-bromo-6-butylbenzo[d]thiazole in acetic acidat 0° C. was added CrO3 in acetic acid. The reaction mixture was allowedto warm to RT and stirred over 2 days. The reaction was neutralized byaq. sodium bicarbonate and extracted with ethyl acetate, washed withbrine, dried over anhydrous sodium sulfate and concentrated, The crudeproduct was purified by preparative TLC to afford1-(2-bromobenzo[d]thiazol-6-yl)butan-1-one. MS (ESI⁺) m/z 286.2 [M+2]⁺

Step-4: A degassed mixture of 2-bromo-6-butylbenzo[d]thiazole (142 mg,0.5 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (135 mg, 0.75 mmol),Pd₂(dba)₃ (9 mg, 0.01 mmol), Xphos (9.5 mg, 0.02 mmol), potassiumphosphate (207 mg, 1.5 mmol) in dioxane (2 mL) under nitrogen atmospherewas stirred at 100° C. for 6 h. The reaction mixture was cooled to RT,evaporated and extracted with dichloromethane, washed with brine, driedover anhydrous sodium sulfate and evaporated. The crude product waspurified by preparative TLC to afford methyl4-(6-butyrylbenzo[d]thiazol-2-yl)benzoate, MS (ESI⁺) m/z 340.2 [M+1]⁺

Step-5: A mixture of methyl methyl4-(6-butyrylbenzo[d]thiazol-2-yl)benzoate (19 mg, 0.05 mmol) and NaBH4(2 mg, 0.5 mmol) in methanol was stirred at RT overnight. The reactionwas quenched with water and evaporated. Water was added and extractedwith DCM and purified by preparative TLC to afford methyl4-(6-(1-hydroxybutyl)benzo[d]thiazol-2-yl)benzoate.

Step-6: A solution of 4-(6-(1-hydroxybutyl)benzo[d]thiazol-2-yl)benzoate(43 mg, 0.126 mmol) in acetonitrile (4 mL) was treated withcarbonylditriazole (29 mg, 0.176 mmol) and stirred at 50° C. over theweekend. The solution was concentrated in vacuo and the residue waspartitioned between water and ethyl acetate. The organic extract wasdried over MgSO₄, filtered and then concentrated. The crude product waspurified by preparative TLC using 5% MeOH in DCM as eluent to affordMethyl4-(6-(1-(1H-1,2,4-triazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate. MS(ES+): m/z 393.27 (MH⁺).

Following the general procedures described above, the followingcompounds were synthesized:

Example-326-(2-(Ethylmethyl)amino)-1-(1H-imidazol-1-yl)butylbenzo[d]thiazol-2-amine

ESI: m/z 330.26 [M+1⁺].

Example-33Methyl-4-(4-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate

MS (ESI⁺) m/z 464.23 [M+H]⁺

Example-34Isopropyl-4-(4-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)benzo[d]thiazol-2-yl)amino)methyl)benzoate

MS (ESI⁺) m/z 492.24 [M+H]⁺.

Example-354-(((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid

MS (ESI⁺) m/z 450.23 [M+H]⁺

Example-361-(2-Bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine

MS ESI: m/z 393.14 [M⁺].

Example-371-(2-Chlorobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine

MS ESI: m/z 335.2 [M+H⁺].

Example-38Methyl-3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate

MS (ESI⁺) m/z 450.19 [M+H]⁺

Example-393-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicacid

MS (ESI⁺) m/z 436.22 [M+H]⁺

Example-40 Methyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate

MS (ESI⁺) m/z 478.15 [M+H]⁺

Example-413-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid

MS (ESI) m/z 464.11 [M+H]⁺

Example-42 Ethyl1-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)carbamoyl)cyclobutanecarboxylate

MS (ESI⁺) m/z 470.21

Example-431-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)carbamoyl)cyclobutanecarboxylicacid

MS (ESI⁺) m/z 442.18 [M+H]⁺

Example-44 Methyl1-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclohexanecarboxylate

MS (ESI⁺) m/z 484.11 [M+H]⁺

Example-451-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclohexanecarboxylicacid

MS (ESI⁺) m/z 492.09 [M+Na]⁺

Example-46 Methyl1-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopentanecarboxylate

MS (ESI⁺) m/z 470.12 [M+H]⁺

Example-471-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopentanecarboxylicacid

MS (ESI⁺) m/z 478.09 [M+Na]⁺

Example-48 Methyl5-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-5-oxopentanoate

MS (ESI⁺) m/z 472.14 [M+H]⁺

Example-495-((6-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-5-oxopentanoicacid

MS (ESI⁺) m/z 458.13 [M+H]⁺

Example-50 Methyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopropanecarboxylate

MS (ESI+) m/z 442.10 [M+H]+

Example-511-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopropanecarboxylicacid

MS (ESI+) m/z 426 [M−1]

Example-52N-(6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)bicyclo[2.2.1]heptane-2-carboxamide

MS (ESI⁺) m/z 460.10 [M+Na]⁺

Example-53 Methyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate

MS (ESI⁺) m/z 450.20 [M]⁺

Example-543-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoicacid

MS (ESI⁺) m/z 437.21 [M+H]⁺

Example-55 Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate

MS (ESI⁺) m/z 435.11 [M+H]

Example-563-(6-(2-(Dimethylamino)-1-(1-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid

MS (ESI⁺) m/z 421.15 [M+H]⁺

Example-57 Methyl4-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate

MS (ESI⁺) m/z 449.16 [M+H]⁺

Example-584-(6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid

MS (ESI⁺) m/z 435.22 [M+H]⁺

Example-59 Methyl3-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate

MS (ESI⁺) m/z 449.16 [M+H]⁺

Example-603-(6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid

MS (ESI⁺) m/z 435.25 [M+H]⁺

Example-61 Methyl2-chloro-4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]imidazol-2-yl)benzoate

MS (ESI⁺) m/z 469.14 [M+H]⁺

Example-622-Chloro-4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid

MS (ESI⁺) m/z 455.13 [M+H]⁺

Example-63 Methyl2-chloro-5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate

MS (ESI⁺) m/z 469.16 [M+H]⁺

Example-642-Chloro-5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid

MS (ESI⁺) m/z 455.17 [M+H]⁺

Example-65 Methyl5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2-fluorobenzoate

Ms (ESI) m/z 453.18 [M+H]⁺

Example-665-(6-(2(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2-fluorobenzoicacid

MS (ESI⁺) m/z 439.16 [M+H]⁺

Example-67 Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-fluorobenzoate

MS (ESI⁺) m/z 453.2 [M+H]⁺

Example-683-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-fluorobenzoicacid

MS (ESI⁺) m/z 439.19 [M+H]⁺

Example-69 Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-(trifluoromethyl)benzoate

MS (ESI⁺) m/z 503.22 [M+H]⁺

Example-703-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-(trifluoromethyl)benzoicacid

MS (ESI⁺) m/z 489.19 [M+H]⁺

Example-711-(2-(4-(2H-Tetrazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine

MS (ESI) 445.24 [M+H]⁺

Example-721-(2-(4-(2H-Tetrazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine

MS (ESI⁺) m/z 445.24 [M+H]⁺

Example 73 Methyl2-chloro-5-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate

MS (ESI⁺) m/z 454.24 [M+H]⁺

Example-742-Chloro-5-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid

MS (ESI⁺) 440.21 [M+H]⁺

Example-75 6-(1-(1H-1,2,4-triazol-1-yl)butyl)-2-bromobenzo[d]thiazole

MS (ESI⁺) m/z 339.13 [M+H]⁺

Example 76 Biological Activity In Vitro

CYP26 Inhibition.

Compounds of formula (I) were tested for activity in a substratedepletion assay for ATRA metabolism in mouse microsomes. Mousemicrosomes were produced by Xenotech from the livers of mice treatedwith ATRA for four days to induce CYP26. ATRA metabolism in thesemicrosomes was tested at a final concentration of 0.1 mg protein/mL in a100 mM phosphate buffer (pH 7.4) containing an NADPH regenerating system(BD Biosciences catalog #451200 and 451220). The assay was run in a 100μL reaction volume and stopped with an equal volume of methanol ATRAconcentrations at the beginning and end of incubations were determinedusing HPLC and LC-MS/MS. The “induced” mouse microsomes have vastlyincreased CYP26 transcription and ATRA metabolic activity compared tonormal microsomes (˜100 fold) and ATRA metabolic activity displaysclassical Michaelis-Menten kinetics with a Km of ˜4 nM, which is similarto the Km reported for the human recombinant enzyme (˜10 nM). At astarting ATRA concentration of approximately 10 nM and under conditionsof significant substrate turnover, inventive compound completelyinhibits ATRA metabolism with an IC₅₀ of 2 nM. Other compounds offormula (I) are similarly potent, for example with an IC₅₀ of 1.6 nM.Most of the inventive compounds showed IC50 of <1.0 uM.

CYP17 Inhibition.

In vitro assays for CYP17 17α hydroxylase and C_(17,20) lyase activityusing rat and dog testis microsomes and ELISA kits from commercialvendors for the detection of formed products were employed. Incubationof rat testis microsomes with the substrate progesterone (P4) results,through the CYP17 17α hydroxylase and C_(17,20) lyase activities, in amarked production of androstenedione (AD) in a time and enzymeconcentration dependent manner. This activity was shown to be completelyinhibited by a positive control compound, abiraterone acetate. Inanother control, microsomes isolated from rat livers, which are known toexpress very little or no CYP17, were shown to be devoid of thisactivity. Assays were also used that determine the activity of 17αhydroxylase activity using P4 as a substrate and detecting HOP4 as aproduct (using dog testis microsomes) and the activity of C₁₇₋₂₀ lyaseby using HOP4 as a substrate and AD as a product (rat testismicrosomes).

The following compounds of Formula (I) inhibited CYP26 with an IC₅₀ of<1.0 μM:

N-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)bicyclo[2.2.1]heptane-2-carboxamide;Methyl4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl4-(6-(2-ethyl-1-(H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;2-chloro-5-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;1-(2-(3-(2H-Tetrazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine,1-(2-(4-(2H-Tetrazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;3-(((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid;3-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoicacid;346-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicadd;4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid;4-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicacid;1-((6-ethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutanecarboxylicacid;1-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclohexanecarboxylicacid;1-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopentanecarboxylicacid;3-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid;4-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-4-oxobutanoicacid;4-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid;5-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-5-oxopentanoicacid.3-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoicacid; and4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoicacid;2-Chloro-4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;2-Chloro-5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-(trifluoromethyl)benzoicacid;3-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-fluorobenzoicacid;3-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;4-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;4-(6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;4-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;5-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2-fluorobenzoicacid;2Chloro-5-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;1-(2-Bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;and6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;

The following compounds of Formula (I) inhibited CYP17 with an IC₅₀ of<5.0 μM;

2-Bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;1-(2-Bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylate;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;1-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea;N-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide;Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carbimidate;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxamide;1-(2-Bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine;1-(2-Chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine;1-(Benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;and6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-4)butyl)benzo[d]thiazol-2-amine.

The following compounds of Formula (I) inhibited CYP19 with an IC₅₀ of<1.0 μM:

2-Bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;1-(2-Bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylate;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine:1-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea;N-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide;Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carbimidate;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxamide;1-(2-Bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine;1-(2-Chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine;1-(Benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;and6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine.

Certain inventive compounds show a marked pharmacodynamic effect inrodents of increasing serum ATRA levels. Serum ATRA concentrationobserved 2 hours after dosing of compounds with CYP26 activity in the1-5 nM range correlated strongly with the pharmacokinetic properties ofthe compounds.

Selectivity for other P450 enzymes. To assess the selectivity ofcompounds embodied herein, activity was evaluated first against CYP3A4and CYP 19 using commercially available recombinant enzymes and assaykits. To calculates a selectivity factor, the IC₅₀ for a particular P450enzyme was divided by the IC₅₀ in the CYP17 combination assay. Compoundswere demonstrated to have selectivity against CYP3A4 and CYP19.

Pharmacokinetic properties. Oral PK studies were conducted on compoundsembodied herein. They showed excellent aqueous solubility (>10 mg/mL insaline) and were dosed at 10 mg/kg in C57BL/6 mice. At varioustime-points from 15 minutes to 8 hours after dosing, serum samples werecollected and determined compound concentrations by LC-MS/MS analysis.

Example 77 Biological Activity In Vivo: Fibrosis

To demonstrate that compounds embodied herein have anti-fibroticactivity in vivo, the TAA-induced liver fibrosis model in mice was used.Mice were treated with thioacetic acid (TAA) for 9 weeks (200 mg/kg, ip,three times a week) and then treated with compound for 4 weeks (10mg/kg, po, qd) while continuing to give TAA. At sacrifice (after a totalof 13 weeks) serum was collected for the determination of liver enzymeactivity and livers for the determination of liver collagen content andliver histopathology. The body weight in inventive compound treatedanimals was markedly increased versus TAA-exposed vehicle treatedanimals (from 25.5±1.5 to 27.4±2.0 grams; p<0.01), indicating an overallbeneficial effect on animal health. As shown in FIG. 1 test compound(TC) treatment had marked effects on reducing the TAA-induced elevationin liver hydroxyproline content (μg/g liver weight; **p<0.01) and onserum levels of AST and ALT, two key indicators for liver function(**p<0.01). These data demonstrate the anti-fibrotic activity ofcompounds of the invention.

Example 78 Biological Activity In Vivo: Reduction in Testosterone Levels

To test whether inventive compounds can reduce serum testosteronelevels, male C57BL/6 mice were dosed with compound (oral, 50 mg/kg) andafter 4 hours serum was collected and analysed for testosterone levels.For comparison, serum from male control mice that were not treated withcompound and of age-matched female mice were tested. Testosterone wasdetermined with an ELISA kit from R&D Systems (Catalog #KGR010).Compound administration resulted in a marked reduction of serumtestosterone levels (FIG. 2). Levels were almost down to the levels infemale control animals.

1-85. (canceled)
 86. A method for the prevention, treatment or lesseningof the severity of a condition or disease associated with orcharacterized by increased, excessive or inappropriate fibrosis, orcancer, emphysema, atherosclerosis, or a neurological disordercomprising administering to a subject in need thereof a compound or apharmaceutical composition comprising a compound represented by Formula(I):

or an E or Z isomer thereof, syn or anti isomer thereof, an opticallypure isomer thereof, or pharmaceutically acceptable salt thereof,wherein: X is an unsaturated heterocycle selected from pyrrolyl,pyrazolyl, imidazolyl, triazolyl, benzimidazolyl, benzotriazolyl,tetrazolyl, thiazole, 3-pyridinyl or 4-pyridinyl, any of which isoptionally substituted with one or more independent R⁶⁶ substituents; R¹is hydrogen, C₀₋₆alkyl, —OR⁷, —SR⁷, or —NR⁷R⁸; R² and R³ are eachindependently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl,C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,diC₁₋₆-aminocarbonyl, mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, orC₁₋₁₀alkyl(aryl)aminocarbonyl, any of which is optionally substitutedwith one or more independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,—SO₂NR⁷¹R⁸¹, or —NR⁷¹R⁸¹ substituents; or aryl-C₀₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is optionallysubstituted with one or more independent halo, cyano, nitro, —OR⁷¹,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which isoptionally substituted with one or more independent halo, cyano, nitro,—OR⁷¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CONR⁷¹R⁸¹, —SO₂NR⁷¹R⁸¹ or —NR⁷¹R⁸¹ substituents; or R² and R³ takentogether with the carbon atom to which they are attached form a 3-10membered saturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent C₁₋₆alkyl, halo, cyano, nitro, —OR⁷⁷—SO₂NR⁷¹R⁸¹ or—CONR⁷¹R⁸¹ substituents; G¹ is hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, —OR⁷², —SR⁷², —NR⁷²R⁸², or G¹ and R³ taken together withthe carbon atom to which they are attached form a 3-10 memberedsaturated ring, unsaturated ring, heterocyclic saturated ring, orheterocyclic unsaturated ring, wherein an N heteroatom of theheterocyclic saturated ring or heterocyclic unsaturated ring optionallyis substituted with an R⁷² substituent; or in the case of —NR⁷²R⁸², R⁷²and R⁸² taken together with the nitrogen atom to which they are attachedform a 3-10 membered heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted with oneor more independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,—SO₂NR⁷³R⁸³ or —NR⁷³R⁸³ substituents; Y is a bond, hydrogen, halogen, anoxygen atom, sulfur atom, —CN, R⁷⁴, —C(═NR⁷⁴)NR⁷⁵R⁷⁶, —C(═NR⁷⁴)OR⁷⁵—,—COR⁷⁴, —R⁷⁴COR⁷⁵, —CR⁷⁴R⁷⁵COR⁷⁶, —COOR⁷⁴, —R⁷⁴COOR⁷⁵, —CR⁷⁴R⁷⁵COOR⁷⁶,—CONR⁷⁴R⁷⁵, —CR⁷⁴R⁷⁵CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵, —NR⁷⁴COR⁷⁵, —NR⁷⁴CONR⁷⁵R⁷⁶,—SO₂NR⁷⁴CONR⁷⁵, —SO₂NR⁷⁴R⁷⁵, —NR⁷⁴SO₂NR⁷⁵R⁷⁶, —NR^(6b)CO—, —NR^(6b)R⁷⁵,aryl or heteroaryl, any of which is optionally substituted with one ormore independent halo, cyano, hydroxy, nitro, R⁶⁸, —SO₂N^(R6)R⁸⁶ or—NR⁷⁶R⁸⁶ substituents; Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-,-arylalkenyl-, -alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-,-hetarylalkenyl-, or -alkenylhetaryl-, any of which is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,R⁶⁸, C₁₋₁₀alkoxy, —COOR⁷⁴, —(C═O)N(R⁷⁴)—, —NR⁷⁴CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵,—SO₂N^(R6)R⁸⁶, —NR⁷⁴SO₂NR⁷⁴R⁷⁵, or —NR⁷⁶R⁸⁶ substituents; Q¹ isC₀₋₆alkyl, cycloC₃₋₈alkyl, bridged bicycloalkyl, —OR⁷⁵, —COR⁷⁴,—NR⁷⁵R⁸⁵, —CO₂R⁷⁵, —CONR⁷⁵R⁸⁵, —(C═S)OR⁷⁵, —(C═O)SR⁷⁵, —NO₂, —CN, halo,—S(O)_(n6)R⁷⁵, —SO₂NR⁷⁵R⁸⁵, —NR⁷⁵(C═NR⁷⁷⁵)NR⁷⁷⁷⁵R⁸⁵,—NR⁷⁵(C═NR⁷⁷⁵)OR⁷⁷⁷⁵, —NR⁷⁵(C═NR⁷⁷⁵)SR⁷⁷⁷⁵, —O(C═O)OR⁷⁵, —O(C═O)NR⁷⁵R⁸⁵,—O(C═O)SR⁷⁵, —S(C═O)OR⁷⁵, —S(C═O)NR⁷⁵R⁸⁵, —S(C═O)SR⁷⁵—NR⁷⁵(C═)NR⁷⁷⁵R⁸⁵,or —NR⁷⁵(C═S)NR⁷⁷⁵R⁸⁵; in the case of —NR⁷⁵R⁸⁵, R⁷⁵ and R⁸⁵ takentogether with the nitrogen atom to which they are attached form a 3-10membered heterocyclic saturated ring; or heterocyclic unsaturated ring,any of which is optionally substituted with one or more independenthalo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂N^(R6)R⁸⁶ or —NR⁷⁶R⁸⁶substituents; R^(4a), R^(4b), R^(4c), R^(5a), R^(5b) and R^(5c) are eachindependently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkyl_(C1-10)alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷R⁸⁷ or—NR⁷⁷R⁸⁷ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, oraryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; orhetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, anyof which is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or —NR⁷⁷R⁸⁷ substituents; ormono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or—N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —OR, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷R⁸⁷, —SO₂NR⁷⁷R⁸⁷ or—NR⁷⁷R⁸⁷ substituents; or R^(4a) with R^(5a), or R^(4b) with R^(5b), orR^(4c) with R^(5C), taken together with the respective carbon atom towhich they are attached, form a carbonyl or 3-10 membered saturated orunsaturated monocyclic or polycyclic ring, wherein said ring isoptionally substituted with R⁶⁹; or R^(4a) with R^(5a), or R^(4b) withR^(5b), or R^(4c) with R^(5c), taken together with the respective carbonatom to which they are attached, form a 3-10 membered saturated orunsaturated monoheterocyclic or polyheterocyclic ring, wherein said ringis optionally substituted with R⁶⁹; R^(6a), R^(6b), R⁶⁶, R⁶⁷, R⁶⁸, andR⁶⁹ are each independently hydrogen, halo, —OR, —SH, —NR⁷⁷R⁸⁸, —CO₂R⁷⁸,—CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₀₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, cyano, nitro, —OR77⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or—NR⁷⁷⁸R⁸⁸⁸ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, oraryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)amino C₁₋₆alkyl,di(aryl)aminoC₁₋₆alkyl, —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which isoptionally substituted with one or more independent halo, cyano, nitro,—OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the caseof —NR⁷⁸R⁸⁸, R⁷⁸ and R⁸⁸ taken together with the nitrogen atom to whichthey are attached form a 3-10 membered mono or polycyclic saturatedring, mono or polycyclic unsaturated ring, wherein said ring isoptionally substituted with one or more independent halo, cyano,hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸ substituents;R⁷, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁷⁵, R⁷⁷⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁷⁸, R⁸, R⁸¹,R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁸⁸, R⁹, R⁹⁵ and R⁹⁸ are eachindependently hydrogen, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl,C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, mono C₁₋₆alkylamino carbonyl,diC₁₋₆alkylaminocarbonyl, mono(aryl)aminocarbonyl,di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which isoptionally substituted with one or more independent halo, cyano,hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; aryl-C₀₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is optionallysubstituted with one or more independent halo, cyano, nitro,—O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which isoptionally substituted with one or more independent halo, cyano, nitro,—O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or—N(C₀₋₄alkyl)(CO₀₋₄alkyl) substituents; ormono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or—N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl) or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; and n1, n2, n3, n4, n6, and n7are each independently equal to 0, 1 or
 2. 87. The method of claim 86wherein X is imidazolyl, triazolyl, 3-pyridinyl or 4-pyridinyl.
 88. Themethod of claim 86 wherein G¹ is hydrogen, di(C₁₋₆alkyl)amino orsaturated heterocycle.
 89. The method of claim 86 wherein R² and R³ areindependently C₀₋₁₀alkyl.
 90. The method of claim 86 wherein Q¹ is —COOHor —COOR⁷⁵.
 91. The method of claim 86 represented by Formula (II):


92. The method of claim 91, selected from the group consisting of:3-(((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid;3-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoicacid;3-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicacid;4-(((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoicacid;4-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoicacid; Isopropyl3-(((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;Isopropyl4-(((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;Ethyl3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;Methyl3-(((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;Isopropyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoate;Methyl3-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate;Methyl4-(((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoate;and Methyl4-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate.93. The method of claim 86 represented by Formula (III):


94. The method of claim 93, selected from the group consisting of:1-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutanecarboxylicacid;1-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclohexanecarboxylicacid;1-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopentanecarboxylicacid;3-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid;4-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-4-oxobutanoicacid;4-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoicacid;1-((6-((1R)-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopropanecarboxylicacid;5-((6-(-2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-5-oxopentanoicacid; Ethyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutanecarboxylate;Methyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclohexanecarboxylate;Methyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopentanecarboxylate;Methyl3-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate;Methyl4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate;Methyl1-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopropanecarboxylate;Methyl5-((6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)-2,2-dimethyl-5-oxopentanoate;andN-(6-(-2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)bicyclo[2.2.1]heptane-2-carboxamide.95. The method of claim 86 represented by Formula (IV):


96. The method of claim 95 selected from the group consisting of: Methyl3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate;Methyl4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate;3-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoicacid; and4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoicacid.
 97. The compound of claim 86 represented by Formula (V):

wherein B is aryl or heteroaryl which is optionally substituted with oneor more independent halo, —OR⁷⁷—SR⁷⁷, —NR⁷⁷R⁸⁸, —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,—NO₂, —CN, —S(O)_(n7)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, cycloC₃₋₈ alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈ alkylC₂₋₁₀ alkenyl, cycloC₃₋₈ alkenylC₂₋₁₀alkenyl, cycloC₃₋₈ alkylC₂₋₁₀alkynyl, cycloC₃₋₈ alkenylC₂₋₁₀ alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀ alkynyl; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, oraryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸ or —NR⁷⁷⁸R⁸⁸⁸substituents.
 98. The compound of claim 97 wherein B is optionallysubstituted phenyl.
 99. The compound of claim 97 selected from the groupconsisting of:2-Chloro-4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;2-Chloro-5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-(trifluoromethyl)benzoicacid;3-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-fluorobenzoicacid;34642-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;3-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid; 4-(6-(1-(1H-1,2,4-Triazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid; 4-(6-(1-(Pyridin-3-yl)butyl)benzo[d]thiazol-2-yl)benzoic acid;4-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;4-(6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;4-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid;5-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2-fluorobenzoicacid; Methyl2-chloro-4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl2-chloro-5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-(trifluoromethyl)benzoate;Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-5-fluorobenzoate;Methyl3-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl3-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl3-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl4-(6-(1-(1H-1,2,4-triazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl 4-(6-(1-(pyridin-3-yl)butyl)benzo[d]thiazol-2-yl)benzoate; Methyl4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl4-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;Methyl5-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2-fluorobenzoate;1-(2-(3-(2H-Tetrazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;1-(2-(4-(2H-Tetrazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;methyl2-chloro-4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;methyl2-chloro-5-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate;2-(4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)phenyl)aceticacid; methyl2-(4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)phenyl)acetate;2-chloro-4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid; and2-chloro-5-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoicacid.
 100. The method of claim 86 represented by Formula (VI):

wherein Y is hydrogen, halogen, —OR⁷⁴, —SR⁷⁴, —R⁷⁴, —C(═NR⁷⁴)NR⁷⁵R⁷⁶,—CN, —C(═NR⁷⁴)OR⁷⁵—, —COR⁷⁴, —R⁷⁴COR⁷⁵, —CR⁷⁴R⁷⁵COR⁷⁶, —COOR⁷⁴,—R⁷⁴COOR⁷⁵, —CR⁷⁴R⁷⁵COOR⁷⁶, —CONR⁷⁴R⁷⁵, —CR⁷⁴R⁷⁵CONR⁷⁴R⁷⁵, —NR⁷⁴COOR⁷⁵,—NR⁷⁴COR⁷⁵, —NR⁷⁴CONR⁷⁵R⁷⁶, —SO₂CR⁷⁴R⁷⁵, —SO₂NR⁷⁴R⁷⁵, —NR⁷⁴SO₂NR⁷⁵R⁷⁶,—NR⁷⁴R⁷⁵, aryl or heteroaryl.
 101. The method of claim 100 wherein Y isH, —COOH, —COOCH₃, —C(═NH)OCH₃, —NHCOOEt, —CONH₂, —CONHCH₃, —NHCOCH₃,—Br, —Cl, —NH₂, —OH, —OCH₃, —NHCONH₂, —COCF₃, -phenyl, —CH₃, or—CH₂COOH.
 102. The method of claim 100, selected from the groupconsisting of:6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylicacid; 6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylicacid; Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylate;Methyl6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carbimidate;Ethyl(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamate;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxamide;N-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide;1-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea;1-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2,2,2-trifluoroethanone;1-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)-2,2,2-trifluoroethanone;1-(1H-Imidazol-1-yl)-N,N-dimethyl-1-(2-phenylbenzo[d]thiazol-6-yl)butan-2-amine;1-(2-Bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;1-(2-Bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine;1-(2-Chlorobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;1-(2-Chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine;1-(Benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;6-(2-(Ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2(3H)-one;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2(3H)-one;1-(1H-Imidazol-1-yl)-1-(2-methoxybenzo[d]thiazol-6-yl)-N,N-dimethylbutan-2-amine;1-(1H-Imidazol-1-yl)-N,N-dimethyl-1-(2-methylbenzo[d]thiazol-6-yl)butan-2-amine;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)-2-methoxybenzo[d]thiazole;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)-2-methylbenzo[d]thiazole;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine;2-Bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole;6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)-2-phenylbenzo[d]thiazole;2-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)aceticacid; 6-(1-(1H-1,2,4-Triazol-1-yl)butyl)-2-bromobenzo[d]thiazole and2-(6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)aceticacid.
 103. The method of claim 86 wherein the disease or condition isfibrotic liver disease, hepatic ischemia-reperfusion injury, cerebralinfarction, ischemic heart disease, renal disease or lung (pulmonary)fibrosis, liver fibrosis associated with hepatitis C, hepatitis B, deltahepatitis, chronic alcoholism, non-alcoholic steatohepatitis,extrahepatic obstructions (stones in the bile duct), cholangiopathies(primary biliary cirrhosis and sclerosing cholangitis), autoimmune liverdisease, and inherited metabolic disorders (Wilson's disease,hemochromatosis, and alpha-1 antitrypsin deficiency); damaged and/orischemic organs, transplants or grafts; ischemia/reperfusion injury;stroke; cerebrovascular disease; myocardial ischemia; renal failure;renal fibrosis, idiopathic pulmonary fibrosis, treatment of wounds foracceleration of healing; vascularization of a damaged and/or ischemicorgan, transplant or graft; amelioration of ischemia/reperfusion injuryin the brain, heart, liver, kidney, and other tissues and organs;normalization of myocardial perfusion as a consequence of chroniccardiac ischemia or myocardial infarction; development or augmentationof collateral vessel development after vascular occlusion or to ischemictissues or organs; fibrotic diseases; hepatic disease including fibrosisand cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosissecondary to renal obstruction; renal trauma and transplantation; renalfailure secondary to chronic diabetes and/or hypertension; amytrophiclateral sclerosis, muscular dystrophy, scleroderma, chronic obstructivepulmonary disease, diabetes mellitus, multiple sclerosis, trauma to thecentral nervous system, Parkinson's disease, Alzheimer's disease, andhereditary neurodegenerative disorders including the leukodystrophiessuch as metachromatic leukodystrophy, Refsum's disease,adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavandisease, Pelizaeus-Merzbacher disease and Alexander's disease.
 104. Themethod of claim 86 wherein the condition or disease is cancer,psoriasis, an inflammatory joint disease or an inflammatory skindisease.
 105. The method of claim 86 wherein the condition or disease isactinic keratoses, arsenic keratoses, inflammatory acne,non-inflammatory acne, psoriasis, ichthyoses, keratinization of theskin, hyperproliferative disorder of the skin, eczema, atopicdermatitis, Darriers disease, lichen planus; glucocorticoid damage tothe skin, age damage to the skin, or photo damage to the skin.
 106. Themethod of claim 86 wherein the prevention, treatment or lessening of theseverity of a condition or disease is associated with modulation ofATRA, androgen or estrogen levels.